TW202130634A - Chemical compounds - Google Patents

Abstract

The invention relates to benzimidazoles of Formula (I)

and pharmaceutically acceptable salts thereof, wherein R¹ to R⁶ are as defined in the description; to their use in medicine; to compositions containing them; to processes for their preparation; and to intermediates used in such processes. The benzimidazoles of Formula (I) are ITK inhibitors and are therefore potentially useful in the treatment of a wide range of disorders including, atopic dermatitis.

Description

Compound

The present invention relates to benzimidazole derivatives, their medical uses, compositions containing them, their preparation methods and intermediates used in these methods. More particularly, the present invention relates to inhibitors of interleukin-2 inducible T cell kinase (ITK) and their use in the treatment of ITK-mediated diseases, especially skin diseases (such as dermatitis, such as atopic dermatitis) In the use.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease prevalent in both children and adults. AD patients suffer from dry and itchy skin lesions that can greatly affect their quality of life. Genetic and environmental factors can cause skin barrier destruction and excessive immune activation, and these effects are the key drivers of the pathogenesis of AD.

The clinical development of dupilumab has demonstrated the pathogenic effects of T cell and Th2 cell-derived interleukins IL-4 and IL-13 in AD. Dupilumab blocks IL-4 And IL-13 both active IL-4 receptor antibody. The important activities of these cytokines are also consistent with the early clinical efficacy observed with Janus kinase (JAK) inhibitors, which block IL-4 and IL-13 and are produced in the skin The signal transduction of other inflammatory cytokines. The therapeutic strategy that can effectively control the production of IL-4 and IL-13 is an alternative way to regulate this pathway. In addition, Th1 cells, Th22 cells and Th17 cells and their respective cytokines IFNγ, IL-22 and IL-17 also contribute to the pathogenesis of AD.

Effective anti-inflammatory agents for AD will modulate the main inflammatory response driven by T cells. Interleukin-2-inducible T cell kinase (ITK) is a member of the Tec tyrosine kinase family. ITK performance is greatly limited by immune cells (such as T cells, natural killer (NK) cells, natural killer T (NKT) cells, and mast cells). In T cells, ITK amplifies T cell receptor (TCR) dependent signals to promote T cell activation, cytokine production, and T cell proliferation. ITK deletion or inhibition of ITK activity in T cells can inhibit the production of IL-4 and IL-13 induced by TCR, the latter playing a major role in the physiology of AD cases. ITK inhibitors are expected to have additional efficacy compared to IL-4 receptor antagonists, because ITK also helps many pro-inflammatory cytokines (such as IL-2, IL-17, IL-22, IL- 31. TCR-dependent production of IFNγ and TNF-α). In addition, CD8+ T cells lacking ITK showed impaired cytotoxic T lymphocyte expansion, reduced degranulation, and defective cytotoxicity. Mice lacking ITK and/or mice treated with ITK inhibitors showed reduced disease in the models of type I diabetes, lymphoid tissue proliferative diseases, allergies/asthma, and airway hyperresponsiveness. In addition, mice lacking ITK or mice treated with ITK inhibitors showed reduced skin inflammation in the dermatitis model. Elevated levels of ITK are found in peripheral T cells of patients with moderate to severe AD, and ITK manifestations in skin lesions of AD patients are elevated.

In addition, tropomyosin receptor kinase (TRK) is expressed by skin cells such as keratinocytes, neurons, mast cells and basophils. Both TRKA and its ligand nerve growth factor (NGF) are present in the skin and its performance in AD skin lesions has been enhanced. It has been confirmed that the NGF content in the skin lesions of AD patients is related to the severity of itching. It has been confirmed that IL-4 and IL-13, which contribute to the pathogenesis of AD, can enhance the TRKA performance of keratinocytes. In addition to regulating the development and maintenance of neurons, NGF can also sensitize pain receptors and promote skin itching. Itching is the main contributor to reducing the quality of life of AD patients. Therapies that can inhibit itching not only alleviate the patient's pain, but also break the itching-scratch cycle that destroys the barrier, thereby reducing the course and long-term nature of the disease.

NGF is also expressed by non-neuronal cells and has an effect on it. NGF induces the proliferation of keratinocytes, promotes the activation of basophils, stimulates mast cells to degranulate, and causes neuropathic itching and inflammation. In addition, TRKA has been reported on peripheral blood T cells stimulated by TCR and T cells collected from the synovial fluid of arthritis patients, and NGF induces the proliferation of T cells. Therefore, in addition to reducing itching, inhibiting TRKA in the skin can also inhibit dermal inflammation.

These data indicate that ITK inhibitors will inhibit pathogenic T cell responses and reduce the production of cytokines, and thus in various inflammatory and autoimmune diseases (including dermatological conditions, such as atopic dermatitis, contact It has therapeutic value in the treatment of dermatitis, psoriasis, alopecia areata and leukoplakia). In addition, inhibitors of both ITK activity and TRKA activity should be particularly useful for the treatment of dermatological conditions (such as those just mentioned, such as atopic dermatitis).

references Benecke H et al., Expert Opin. Invest. Drugs. 2013; 22:1167-1179; Bissonette R, Papp KA et al., Brit. J. Derm. 2016; 175:902-911; Botchkarev VA, Yaar M, Peters EMJ, et al., J. Invest. Dermatology. 2006; 126:1719-1727; Brunner PM et al., J Allergy Clin Immunol. 2017; 139(4S):S65-S76; Kapnick SM, Stinchcombe JC et al., Immunol. 2017; 198:2699-2711; Lin TA, McIntyre KW et al., Biochemistry 2004; 43:11056-11062; Matsumura S, Terao M, et al., J. Derm. Science 2015; 78:215-223; Otsuka A, Nomura T et al., Immunological Reviews. 2017; 278:246-262; Raychaudhuri SP, Raychaudhuri SK and others, Arthritis & Rheumatism 2011; 63:3243-3252; Sabat R, Wolk K et al., Seminars in Immunopathology 2019; 41:359-377; Sahu N and August A. Curr. Top. Med. Chem. 2009; 9:690-703; Von Bonin A, Rausch A and others, Exp. Derm. 2010; 20:41-47; Yamaguchi J, Aihara M, et al., J. Dermatol. Science. 2008; 53:48-54

或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中 每一R¹ 獨立地係H或F； R² 係H、(C₁ -C₄ )烷基、羥基(C₁ -C₄ )烷基、(C₁ -C₄ )烷氧基(C₁ -C₄ )烷基或由一個、兩個或三個F取代之(C₁ -C₄ )烷基； 每一R³ 獨立地係H、F、(C₃ -C₅ )環烷基、(C₁ -C₄ )烷基或由一個、兩個或三個F取代之(C₁ -C₄ )烷基；或兩個R³ 與其所連接之碳原子一起形成(C₃ -C₅ )環烷基； R⁴ 係

或

，其中每一雜環視情況由一或兩個獨立地選自側氧基、(C₁ -C₄ )烷基、羥基(C₁ -C₄ )烷基及由一個、兩個或三個F取代之(C₁ -C₄ )烷基之取代基取代；且 R⁵ 及R⁶ 獨立地係H；鹵素；OH；CN；(C₁ -C₆ )烷基；羥基(C₁ -C₆ )烷基；(C₁ -C₄ )烷氧基(C₁ -C₆ )烷基；由一個、兩個或三個F取代之(C₁ -C₆ )烷基；(C₁ -C₆ )烷氧基；或由(C₁ -C₄ )烷氧基取代之(C₁ -C₆ )烷氧基。According to the first aspect of the present invention, a compound of formula (I) is provided:

Or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt, wherein each R ^{1 is} independently H or F; R ² is H, (C ₁ -C ₄ )alkyl , Hydroxy (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl or substituted by one, two or three F (C ₁ -C ₄ ) Alkyl; each R ^{3 is} independently H, F, (C ₃ -C ₅ ) cycloalkyl, (C ₁ -C ₄ ) alkyl or substituted by one, two or three F (C _1- C ₄ )alkyl; or two R ³ together with the carbon atoms to which they are connected form (C ₃ -C ₅ ) cycloalkyl; R ⁴ is

or

, Where each heterocyclic ring is optionally composed of one or two independently selected from pendant oxy groups, (C ₁ -C ₄ )alkyl, hydroxy (C ₁ -C ₄ )alkyl, and one, two or three F Substituents of substituted (C ₁ -C ₄ ) alkyl; and R ⁵ and R ^{6 are} independently H; halogen; OH; CN; (C ₁ -C ₆ ) alkyl; hydroxy (C ₁ -C ₆ ) alkyl; (C ₁ -C ₄₎ alkoxy (C ₁ -C ₆₎ alkyl; by one, two or three substituents of F (C ₁ -C ₆₎ alkyl; (C ₁ -C ₆₎ alkoxy; or a substituent of (C ₁ -C ₄₎ alkoxy (C ₁ -C ₆₎ alkoxy.

； 或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E15  如實施例E1至E14中任一項之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁴ 係

或

， 其視情況由一或兩個獨立地選自側氧基、(C₁ -C₄ )烷基及羥基(C₁ -C₄ )烷基之取代基取代。 E16  如實施例E15之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁴ 係

或

， 其視情況由一或兩個獨立地選自側氧基、甲基及羥甲基之取代基取代。 E17  如實施例E16之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁴ 係

或

。 E18  如實施例E17之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁴ 係

。 E19  如實施例E16之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁴ 係

， 其視情況由一或兩個獨立地選自側氧基、甲基及羥甲基之取代基取代。 E20  如實施例E19之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁴ 係

， 其視情況由側氧基取代。 E21  如實施例E19之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁴ 係

， 其視情況由一或兩個甲基取代。 E22  如實施例E19之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁴ 係

。 E23  如實施例E1至E22中任一項之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁵ 及R⁶ 獨立地係H；鹵素；OH；CN；(C₁ -C₃ )烷基；羥基(C₁ -C₃ )烷基；(C₁ -C₃ )烷氧基(C₁ -C₃ )烷基；由一個、兩個或三個F取代之(C₁ -C₃ )烷基；(C₁ -C₃ )烷氧基；或由(C₁ -C₃ )烷氧基取代之(C₁ -C₃ )烷氧基。 E24  如實施例E23之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁵ 係H、鹵素、CN、(C₁ -C₆ )烷基、(C₁ -C₆ )烷氧基或由(C₁ -C₄ )烷氧基取代之(C₁ -C₆ )烷氧基。 E25  如實施例E24之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁵ 係H、鹵素、CN、(C₁ -C₃ )烷基、(C₁ -C₃ )烷氧基或由(C₁ -C₃ )烷氧基取代之(C₁ -C₃ )烷氧基。 E26  如實施例E25之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁵ 係H、F、Br、CN、甲基、乙基、甲氧基或CH₃ O-CH₂ -CH₂ O-。 E27  如實施例E1至E26中任一項之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁶ 係H；鹵素；OH；CN；(C₁ -C₆ )烷基；羥基(C₁ -C₆ )烷基；(C₁ -C₄ )烷氧基(C₁ -C₆ )烷基；由一個、兩個或三個F取代之(C₁ -C₆ )烷基；或(C₁ -C₆ )烷氧基。 E28  如實施例E27之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁶ 係H；鹵素；OH；CN；(C₁ -C₃ )烷基；羥基(C₁ -C₃ )烷基；(C₁ -C₃ )烷氧基(C₁ -C₃ )烷基；由一個、兩個或三個F取代之(C₁ -C₃ )烷基；或(C₁ -C₃ )烷氧基。 E29  如實施例E28之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其中R⁶ 係H、F、Cl、Br、OH、CN、甲基、乙基、羥甲基、甲氧基甲基、CHF₂ 、CF₃ 或甲氧基。 E30  如實施例E1之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其選自： 實例1：(S)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例2：N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例3：(R)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例4：(R)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)丙醯胺； 實例5：N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)丙醯胺； 實例6：(S)-N -乙基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例7：(R)-N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)丙醯胺； 實例8：N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)丙醯胺； 實例9：(S)-N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)丙醯胺； 實例10：N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)乙醯胺； 實例11：2,2-二氟-N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)乙醯胺； 實例12：(R)-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-(四氫-2H -吡喃-4-基)丙醯胺； 實例13：(S)-N -(2-((4aS,5aR)-5,5-二氟-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例14：(S)-N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例15：(S)-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例16：(S)-N -乙基-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例17：(S)-N -(6-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例18：(S)-N -(6-乙基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例19：(S)-N -(6-甲氧基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例20：(S)-N -(6-溴-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例21：(S)-N -(6-氰基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例22：(S)-N-(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H-苯并[d]咪唑-5-基)-N-甲基-2-(3-側氧基-N -𠰌啉基)丙醯胺； 實例23：(R)-N-(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H-苯并[d]咪唑-5-基)-N-甲基-2-(3-側氧基-N -𠰌啉基)丙醯胺； 實例24：(S)-N -(6,7-二氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例25：(S)-N -(6,7-二氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -乙基-2-N -𠰌啉基丙醯胺； 實例26：2-((S)-2-(羥甲基)-N -𠰌啉基)-N -甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)乙醯胺； 實例27：2-(2-(羥甲基)-N -𠰌啉基)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)乙醯胺； 實例28：2-((R )-2-(羥甲基)-N -𠰌啉基)-N -甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)乙醯胺； 實例29：2-(2,2-二甲基-N -𠰌啉基)-N -甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6- 六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)乙醯胺； 實例30：甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-2-((R )-2-甲基-N -𠰌啉基)乙醯胺； 實例31：甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-2-((S)-2-甲基-N -𠰌啉基)乙醯胺； 實例32：2-((2R,6R)-2,6-二甲基-N -𠰌啉基)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)乙醯胺； 實例33：2-((2S ,6S )-2,6-二甲基-N -𠰌啉基)-N -甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)乙醯胺； 實例34：N -甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-2-N -𠰌啉基乙醯胺； 實例35：N -甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)乙醯胺； 實例36：N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(3-側氧基-N -𠰌啉基)乙醯胺； 實例37：(S)-N -(7-溴-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例38：(S)-N -(7-氰基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例39：(S)-N -(7-羥基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例40：(S)-N -(7-甲氧基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例41：(S)-N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-7-(三氟甲基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例42：(S)-N -(7-(甲氧基甲基)-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例43：(S)-N -(7-氯-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例44：(S)-N -(7-乙基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例45：(S)-N -(7-(羥甲基)-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例46：(S)-N -(7-氟-6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例47：(S)-N -(6-氟-7-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例48：(S)-N -(7-(二氟甲基)-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例49：(S)-N -(6-(2-甲氧基乙氧基)-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例50：(S)-N -甲基-N -(7-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-2-N -𠰌啉基丙醯胺；及 實例51：(S)-N -(2-((4aS ,5aR )-5,5-二氟-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-7-甲基-1H -苯并[d ]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺。 E31  如實施例E1之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其選自： 實例52：(S)-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H-苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例53：(S)-N-(2-((4aS,5aR)-5,5-二氟-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-5-甲基-1H-苯并[d]咪唑-6-基)-N-甲基-2-N -𠰌啉基丙醯胺； 實例54：N -(6-氰基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H-苯并[d]咪唑-5-基)-N-甲基-2-(四氫-2H-吡喃-4-基)乙醯胺； 實例55：(R)-N -(7-氰基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H-苯并[d]咪唑-5-基)-N-甲基-2-(四氫-2H-吡喃-4-基)丙烯醯胺；及 實例56：(S)-N-(甲基-¹³ C -d ₃ )-N-(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H-苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺。 E32  如實施例E1之化合物或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物，其選自： 實例1：(S)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例7：(R)-N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)丙醯胺； 實例12：(R)-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-(四氫-2H -吡喃-4-基)丙醯胺； 實例15：(S)-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例16：(S)-N -乙基-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺； 實例24：(S)-N -(6,7-二氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺； 實例25：(S)-N -(6.7-二氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -乙基-2-N -𠰌啉基丙醯胺； 實例46：(S)-N -(7-氟-6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺；及 實例50：(S)-N -甲基-N -(7-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-2-N -𠰌啉基丙醯胺。 E33  如實施例E32之化合物，其係(S)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E34  如實施例E32之化合物，其係(R)-N -甲基-N -(2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-(四氫-2H -吡喃-4-基)丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E35  如實施例E32之化合物，其係(R)-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-(四氫-2H -吡喃-4-基)丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E36  如實施例E32之化合物，其係(S)-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E37  如實施例E32之化合物，其係(S)-N -乙基-N -(7-氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E38  如實施例E32之化合物，其係(S)-N -(6,7-二氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E39  如實施例E32之化合物，其係(S)-N -(6.7-二氟-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-N -乙基-2-N -𠰌啉基丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E40  如實施例E32之化合物，其係(S)-N -(7-氟-6-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-N -甲基-2-N -𠰌啉基丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E41  如實施例E32之化合物，其係(S)-N -甲基-N -(7-甲基-2-((4aS ,5aR )-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1H -苯并[d ]咪唑-5-基)-2-N -𠰌啉基丙醯胺或其醫藥上可接受之鹽或該化合物或該鹽之醫藥上可接受之溶劑合物。 E42  如實施例E33之化合物，其係(S)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺或其醫藥上可接受之溶劑合物。 E43  如實施例E42之化合物，其係(S)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺或其水合物。 E44  如實施例E43之化合物，其係二水合(S)-N -甲基-N -(6-甲基-2-((4aS,5aR)-5a-甲基-1,4,4a,5,5a,6-六氫環丙[f]吲唑-3-基)-1H -苯并[d]咪唑-5-基)-2-N -𠰌啉基丙醯胺。 E45  如實施例E33之化合物，其係

。 E46  一種如實施例E44之化合物之結晶形式。 E47  如實施例E46之結晶形式，其具有一個、兩個、三個、四個或五個選自6.6°±0.2° 2θ、7.4°±0.2° 2θ、11.0°±0.2° 2θ、11.6°±0.2° 2θ、15.7°±0.2° 2θ及17.7°±0.2° 2θ之PXRD峰。 E48  如實施例E47之結晶形式，其具有6.6°±0.2° 2θ、11.0°±0.2° 2θ、15.7°±0.2° 2θ及17.7°±0.2° 2θ處之PXRD峰。 E49  如實施例E47之結晶形式，其具有6.6°±0.2° 2θ、7.4°±0.2° 2θ、11.0°±0.2° 2θ及11.6°±0.2° 2θ處之PXRD峰。 E50  如實施例E47之結晶形式，其具有7.4°±0.2° 2θ、11.6°±0.2° 2θ、15.7°±0.2° 2θ及17.7°±0.2° 2θ處之PXRD峰。 E51  如實施例E47之結晶形式，其具有6.6°±0.2° 2θ、7.4°±0.2° 2θ、11.0°±0.2° 2θ、11.6°±0.2° 2θ、15.7°±0.2° 2θ及17.7°±0.2° 2θ處之PXRD峰。 E52  如實施例E46之結晶形式，其具有6.6°±0.2° 2θ、7.4°±0.2° 2θ、11.0°±0.2° 2θ、11.6°±0.2° 2θ、13.3°±0.2° 2θ、15.7°±0.2° 2θ、16.2°±0.2° 2θ、17.7°±0.2° 2θ、18.8°±0.2° 2θ及22.9°±0.2° 2θ處之PXRD峰。The following describes an embodiment of this first aspect of the present invention, in which E1 is consistent with it for convenience. E1 A compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt, which is as defined above . E2 is the compound of embodiment E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein each R ¹ is H or F. E3 is the compound of Example E2 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein each R ¹ is H. E4 The compound of any one of embodiments E1 to E3 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ² is H or (C ₁ -C ₄ ) alkyl. E5 is the compound of embodiment E4 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ² is H. E6 is the compound of embodiment E4 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ² is a methyl group or an ethyl group. E7 is the compound of embodiment E6 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ² is a methyl group. E8 is the compound of embodiment E6 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ² is an ethyl group. E9 The compound of any one of embodiments E1 to E8 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt, wherein each R ^{3 is} independently H, F or ( C ₁ -C ₄ ) alkyl. E10 is the compound of Example E9 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt, wherein each R ^{3 is} independently H, F or methyl. E11 is the compound of embodiment E10 or a pharmaceutically acceptable salt thereof or the compound or a pharmaceutically acceptable solvate of the salt, wherein each R ³ is F. E12 is the compound of embodiment E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein each R ³ is H. E13 is the compound of embodiment E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein one R ³ is H and the other R ³ is methyl. E14 is the compound of Example E13, which has the formula (Ia):

; Or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt. E15 The compound of any one of embodiments E1 to E14 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

or

, Which is optionally substituted by one or two substituents independently selected from pendant oxy, (C ₁ -C ₄ )alkyl and hydroxy (C ₁ -C ₄ )alkyl. E16 The compound of embodiment E15 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

or

, Which is optionally substituted by one or two substituents independently selected from pendant oxy groups, methyl groups and hydroxymethyl groups. E17 The compound of embodiment E16 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

or

. E18 The compound of embodiment E17 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ⁴ is

. E19 The compound of embodiment E16 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

, Which is optionally substituted by one or two substituents independently selected from pendant oxy groups, methyl groups and hydroxymethyl groups. E20 The compound of embodiment E19 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

, Which is optionally substituted by pendant oxy groups. E21 The compound of embodiment E19 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

, Which is optionally substituted by one or two methyl groups. E22 The compound of embodiment E19 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

. E23 The compound of any one of embodiments E1 to E22 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ⁵ and R ^{6 are} independently H; halogen; OH; CN; (C ₁ -C ₃ ) alkyl; hydroxy (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl; composed of one or two the three F, or substituted (C ₁ -C ₃₎ alkyl; (C ₁ -C ₃₎ alkoxy; or a substituent of (C ₁ -C ₃₎ alkoxy (C ₁ -C ₃₎ alkoxy base. E24 The compound of embodiment E23 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ⁵ is H, halogen, CN, (C ₁ -C ₆ )alkyl , (C ₁ -C ₆₎ alkoxy group or of the substituted (C ₁ -C ₄₎ alkoxy (C ₁ -C ₆₎ alkoxy. E25 The compound of embodiment E24 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁵ is H, halogen, CN, (C ₁ -C ₃ )alkyl , (C ₁ -C ₃ )alkoxy or (C ₁ -C ₃ )alkoxy substituted by (C ₁ -C ₃ )alkoxy. E26 is the compound of embodiment E25 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ⁵ is H, F, Br, CN, methyl, ethyl, methyl Oxy or CH ₃ O-CH ₂ -CH ₂ O-. E27 The compound of any one of embodiments E1 to E26 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁶ is H; halogen; OH; CN; ( C ₁ -C ₆ )alkyl; hydroxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₄ )alkoxy(C ₁ -C ₆ )alkyl; substituted by one, two or three F的(C ₁ -C ₆ )alkyl; or (C ₁ -C ₆ )alkoxy. E28 The compound of embodiment E27 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁶ is H; halogen; OH; CN; (C ₁ -C ₃ ) Alkyl; hydroxy (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl; substituted by one, two or three F (C ₁ -C ₃ ) Alkyl; or (C ₁ -C ₃ )alkoxy. E29 is the compound of embodiment E28 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁶ is H, F, Cl, Br, OH, CN, methyl, Ethyl, hydroxymethyl, methoxymethyl, CHF ₂ , CF ₃ or methoxy. E30 is the compound of Example E1 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, which is selected from: Example 1: (S) -N -methyl- N- ( 6-Methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzene And [d]imidazol-5-yl)-2- N -𠰌linyl propionamide; Example 2: N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl Base-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌line Propyl propanamide; Example 3: (R) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6 -Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linyl propionamide; Example 4: (R) -N -Methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazole-3- yl) -1 H - benzo [d] imidazol-5-yl) -2- (tetrahydro -2 H - pyran-4-yl) propan Amides; example 5: N - methyl - N - (6 -Methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo [d]imidazol-5-yl)-2-(tetrahydro- 2H -pyran-4-yl)propanamide; Example 6: (S) -N -ethyl- N- (6-methyl- 2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazole -5-yl)-2- N -𠰌linylpropionamide; Example 7: (R) -N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4, 4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H -pyran- 4-yl)propanamide; Example 8: N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropyl[ f] indazol-3-yl) -1 H - benzo [d] imidazol-5-yl) -2- (tetrahydro -2 H - pyran-4-yl) propan Amides; example 9: (S ) -N -methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl) -1 H -Benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H -Pyran-4-yl)propanamide; Example 10: N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexa hydrogen cyclopropa [f] indazol-3-yl) -1 H - benzo [d] imidazol-5-yl) -2- (tetrahydro -2 H - pyran-4-yl) acetyl amine; example 11: 2,2-Difluoro- N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropyl[f] Indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2-(tetrahydro- 2H -pyran-4-yl)acetamide; Example 12: (R)- N -(7-Fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -Benzo[d]imidazol-5-yl) -N -methyl-2-(tetrahydro- 2H -pyran-4-yl)propanamide; Example 13: (S) -N -(2- ((4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f)indazol-3-yl)-1 H -benzene And [d]imidazol-5-yl) -N -methyl-2- N- 𠰌lineylpropanamide; Example 14: (S) -N -methyl- N -(2-((4aS,5aR) -5a-Methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linyl propanamide; Example 15: (S) -N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexa Hydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N- 𠰌linylpropanamide; Example 16: (S ) -N -ethyl- N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazole- 3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linylpropionamide; Example 17: (S) -N -(6-fluoro-2-((4aS ,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -Methyl-2- N -𠰌linylpropanamide; Example 18: (S) -N -(6-ethyl-2-((4aS,5aR)-5a-methyl-1,4, 4a,5,5a,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N -𠰌olinyl Propylamine; Example 19: (S) -N -(6-methoxy-2-(( 4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl ) -N -Methyl-2- N -𠰌linylpropanamide; Example 20: (S) -N -(6-bromo-2-((4aS,5aR)-5a-methyl-1,4, 4a,5,5a,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N -𠰌olinyl propan Amides; example 21: (S) - N - (6- cyano -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [ f]Indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N- 𠰌linylpropanamide; Example 22: (S)-N- (7-Fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f)indazol-3-yl)-1H-benzo [d]imidazol-5-yl)-N-methyl-2-(3-oxo- N- 𠰌olinyl)propionamide; Example 23: (R)-N-(7-fluoro-2- ((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f)indazol-3-yl)-1H-benzo(d)imidazole-5- yl) -N- methyl-2- (3-oxo - N - 𠰌 morpholinyl) propan Amides; example 24: (S) - N - (6,7- difluoro -2 - ((4aS, 5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f]indazol-3-yl)-1 H -benzo(d]imidazol-5-yl)- N -Methyl-2- N -𠰌linylpropanamide; Example 25: (S) -N -(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4 ,4a,5,5a,6-hexahydrocyclopropyl[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -ethyl-2- N -𠰌line Amides propan-yl; example 26: 2 - ((S) -2- ( hydroxymethyl) - N - 𠰌 quinazolinyl) - N - methyl - N - (6- methyl -2 - ((4a S, 5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl) as acetamide; example 27: 2- (2- (hydroxymethyl) - N - 𠰌 quinazolinyl) - N - methyl - N - (6- methyl -2 - ((4aS, 5aR) -5a- A Group-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)acetamide; Example 28: 2-(( R )-2-(Hydroxymethyl) -N -𠰌linyl) -N -methyl- N -(6-Methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)- 1 H -Benzo[ d ]imidazol-5-yl)acetamide; Example 29: 2-(2,2-Dimethyl- N- 𠰌olinyl) -N -methyl- N- (6-methyl Base-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo [ d ]imidazol-5-yl)acetamide; Example 30: Methyl- N- (6-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5 ,5a,6-Hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl)-2-(( R )-2-methyl- N -𠰌 (Hydroxy)acetamide; Example 31: Methyl- N- (6-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexa Hydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl)-2-((S)-2-methyl- N -(indazol-3-yl)acetamide ; Example 32: 2-((2R,6R)-2,6-dimethyl- N- 𠰌olinyl) -N -methyl- N- (6-methyl-2-((4aS,5aR)- 5a-Methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)acetamide; Example 33: 2-((2 S ,6 S )-2,6-dimethyl- N -𠰌olinyl) -N -methyl- N -(6-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl)ethyl Amide; Example 34: N -methyl- N- (6-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydro ring Propyl [ f ] indazol-3-yl) -1 H -benzo[ d ]imidazol-5-yl)-2- N -linolinylacetamide; Example 35: N -methyl- N -(6 -Methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H- Benzo[ d ]imidazol-5-yl)-2-(tetrahydro- 2H -pyran-4-yl)acetamide; Example 36: N -methyl- N- (6-methyl-2- ((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f)indazol-3-yl)-1 H -benzene And [d]imidazol-5-yl)-2-(3-pendant oxy- N -𠰌lineyl)acetamide; Example 37: (S) -N -(7-bromo-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl ) -N -Methyl-2- N -𠰌linylpropanamide; Example 38: (S) -N -(7-cyano-2-((4aS,5aR)-5a-methyl-1,4 ,4a,5,5a,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N -𠰌line Amides propan-yl; example 39: (S) - N - (7- hydroxy -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [ f] indazol-3-yl) -1 H - benzo [d] imidazol-5-yl) - N - methyl -2- N - propan Amides 𠰌 quinolyl; example 40: (S) - N - (7-Methoxy-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f)indazol-3-yl)-1 H -Benzo[d]imidazol-5-yl) -N -methyl-2- N- 𠰌linylpropanamide; Example 41: (S) -N -methyl- N -(2-((4aS, 5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-7-(trifluoromethyl)-1 H -benzo[ d]imidazol-5-yl)-2- N -𠰌linylpropanamide; Example 42: (S) -N -(7-(methoxymethyl)-2-((4aS,5aR)-5a -Methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl -2- N -𠰌linyl propanamide; Example 43: (S) -N -(7-chloro-2-((4a S ,5a R )-5a-methyl-1,4,4a,5, 5a, 6-Hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl) -N -methyl-2- N -𠰌linylpropionamide; example 44: (S) - N - (7- ethyl -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazol-3-yl) -1 H - benzo [d] imidazol-5-yl) - N - methyl -2- N - propan Amides 𠰌 quinolyl; example 45: (S) - N - (7 -(Hydroxymethyl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H -Benzo[ d ]imidazole -5-yl) -N -methyl-2- N -𠰌linylpropanamide; Example 46: (S) -N -(7-fluoro-6-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl)- N -Methyl-2- N -𠰌linylpropanamide; Example 47: (S) -N -(6-Fluoro-7-methyl-2-((4aS,5aR)-5a-methyl-1, 4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N -𠰌 Amides propan-morpholinyl; example 48: (S) - N - (7- ( difluoromethyl) -2 - ((4aS, 5aR ) -5a- methyl -1,4,4a, 5,5a, 6 -Hexahydrocyclopropyl[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N -𠰌linylpropanamide; Example 49: (S) -N -(6-(2-Methoxyethoxy)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropane [f]Indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N- 𠰌linylpropanamide; Example 50: (S) -N -Methyl- N -(7-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazole- 3-yl)-1 H -benzo[ d ]imidazol-5-yl)-2- N -𠰌linyl propionamide; and Example 51: (S) -N -(2-((4a S ,5a R )-5,5-Difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-7-methyl-1 H- Benzo[ d ]imidazol-5-yl) -N -methyl-2- N -𠰌linyl propionamide. E31 is the compound of embodiment E1 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, which is selected from: Example 52: (S) -N -(6-methyl- 2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1H-benzo[d] (Imidazol-5-yl)-2- N -𠰌linylpropanamide; Example 53: (S)-N-(2-((4aS,5aR)-5,5-difluoro-5a-methyl-1 ,4,4a,5,5a,6-Hexahydrocycloprop[f]indazol-3-yl)-5-methyl-1H-benzo[d]imidazol-6-yl)-N-methyl- 2- N -𠰌linylpropionyl amine; Example 54: N -(6-cyano-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6- Hexahydrocycloprop[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-(tetrahydro-2H-pyran-4-yl)ethyl Amides; example 55: (R) - N - (7- cyano -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropyloxy [f]Indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-(tetrahydro-2H-pyran-4-yl)propenamide; and Example 56: (S)-N-(methyl- ¹³ C - d ₃ )-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5, 5a, 6-Hexahydrocycloprop[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2- N- 𠰌linylpropionamide. E32 is the compound of embodiment E1 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, which is selected from: Example 1: (S) -N -methyl- N- ( 6-Methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzene And [d]imidazol-5-yl)-2- N -𠰌linyl propionamide; Example 7: (R) -N -methyl- N -(2-((4aS,5aR)-5a-methyl -1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H - pyran-4-yl) propan Amides; example 12: (R) - N - (7- fluoro -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a ,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2-(tetrahydro-2 H -pyran- 4- yl) propan Amides; example 15: (S) - N - (7- fluoro -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro- Cycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N- 𠰌linylpropionamide; Example 16: (S) -N -Ethyl- N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazole-3 -Yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linyl propionamide; Example 24: (S) -N -(6,7-difluoro-2-( (4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f)indazol-3-yl)-1 H -benzo(d)imidazole-5- yl) - N - methyl -2- N - propan Amides 𠰌 quinolyl; example 25: (S) - N - (6.7- difluoro -2 - ((4aS, 5aR) -5a- methyl-1, 4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -ethyl-2- N -𠰌 Amides propan-morpholinyl; example 46: (S) - N - (7- fluoro-6-methyl -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5,5a ,6-Hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl) -N -methyl-2- N -𠰌linylpropanamide; and Example 50: (S) -N -methyl- N- (7-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydro Cycloprop[ f ]indazol-3-yl )-1 H -Benzo[ d ]imidazol-5-yl)-2- N -𠰌linyl propionamide. E33 is the compound of Example E32, which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a ,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linylpropionamide or its pharmaceutically acceptable The salt or the compound or the pharmaceutically acceptable solvate of the salt. E34 is the compound of Example E32, which is (R) -N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydro cyclopropa [f] indazol-3-yl) -1 H - benzo [d] imidazol-5-yl) -2- (tetrahydro -2 H - pyran-4-yl) propan-acyl amine or a pharmaceutically The above acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt. Example E32 The compound of embodiment E35, which line (R) - N - (7- fluoro -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydrocycloocta Propyl[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2-(tetrahydro- 2H -pyran-4-yl)propanol The amine or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt. Example E32 The compound of embodiment E36, which line (S) - N - (7- fluoro -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydrocycloocta Prop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N -linolinyl propionamide or its pharmaceutically acceptable salt Or a pharmaceutically acceptable solvate of the compound or the salt. E37 is the compound of Example E32, which is (S) -N -ethyl- N- (7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a, 6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linylpropionamide or its pharmaceutically acceptable salt Or a pharmaceutically acceptable solvate of the compound or the salt. Example E32 The compound of embodiment E38, which line (S) - N - (6,7- difluoro -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N -𠰌linylpropionamide or its pharmaceutically acceptable The accepted salt or the compound or a pharmaceutically acceptable solvate of the salt. Example E32 The compound of embodiment E39, which line (S) - N - (6.7- difluoro -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro- Cyclopropan[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -ethyl-2- N -𠰌linylpropionamide or its pharmaceutically acceptable The salt or the compound or the pharmaceutically acceptable solvate of the salt. Example E32 The compound of embodiment E40, which line (S) - N - (7- fluoro-6-methyl -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5, 5a, 6-Hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl) -N -methyl-2- N -𠰌linylpropanamide or The pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt. E41 is the compound of Example E32, which is (S) -N -methyl- N- (7-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5 ,5a,6-Hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl)-2- N -𠰌linylpropionamide or its pharmaceutically acceptable The accepted salt or the compound or a pharmaceutically acceptable solvate of the salt. E42 is the compound of Example E33, which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a ,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linylpropionamide or its pharmaceutically acceptable Solvate. E43 The compound of Example E42, which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a ,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linylpropionamide or its hydrate. E44 is the compound of Example E43, which is dihydrate (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5 ,5a,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N -𠰌linylpropionamide. E45 is the compound of Example E33, which is

. E46 A crystalline form of the compound of Example E44. E47 is the crystalline form of embodiment E46, which has one, two, three, four or five selected from 6.6°±0.2° 2θ, 7.4°±0.2° 2θ, 11.0°±0.2° 2θ, 11.6°± PXRD peaks of 0.2° 2θ, 15.7°±0.2° 2θ and 17.7°±0.2° 2θ. E48 is the crystalline form of Example E47, which has PXRD peaks at 6.6°±0.2° 2θ, 11.0°±0.2° 2θ, 15.7°±0.2° 2θ, and 17.7°±0.2° 2θ. E49 is the crystalline form of Example E47, which has PXRD peaks at 6.6°±0.2° 2θ, 7.4°±0.2° 2θ, 11.0°±0.2° 2θ, and 11.6°±0.2° 2θ. E50 is the crystalline form of Example E47, which has PXRD peaks at 7.4°±0.2° 2θ, 11.6°±0.2° 2θ, 15.7°±0.2° 2θ, and 17.7°±0.2° 2θ. E51 is the crystalline form of Example E47, which has 6.6°±0.2° 2θ, 7.4°±0.2° 2θ, 11.0°±0.2° 2θ, 11.6°±0.2° 2θ, 15.7°±0.2° 2θ and 17.7°±0.2 ° PXRD peak at 2θ. E52 is the crystalline form of embodiment E46, which has 6.6°±0.2° 2θ, 7.4°±0.2° 2θ, 11.0°±0.2° 2θ, 11.6°±0.2° 2θ, 13.3°±0.2° 2θ, 15.7°±0.2 ° 2θ, 16.2°±0.2° 2θ, 17.7°±0.2° 2θ, 18.8°±0.2° 2θ and 22.9°±0.2° 2θ PXRD peaks.

In the compound of formula (I): ● Alkyl means a straight or branched hydrocarbon group of _{formula -C n} H _(2n+1). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, and tertiary butyl. ● Alkyloxy means an alkyl substituent connected via an oxygen atom. Examples of alkyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, and tertiary butoxy. ● Cycloalkyl means a cyclic hydrocarbon group _{of formula -C n} H _(2n-1) containing at least three carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl. ● Examples of halogen include fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). ● Pendant oxygen refers to double bond oxygen (=O).

In the following, all the compounds of the present invention mentioned include a compound of formula (I) or a pharmaceutically acceptable salt, solvate or multi-component complex thereof or a pharmaceutically acceptable salt of a compound of formula (I). The above acceptable solvates or multi-component complexes are discussed in more detail below.

The preferred compound of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt.

Other preferred compounds of the present invention are compounds of formula (I) or pharmaceutically acceptable solvates thereof.

Other preferred compounds of the present invention are compounds of formula (I) or pharmaceutically acceptable hydrates thereof.

Suitable acid addition salts are formed by acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citric acid Salt, cyclohexamine sulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, Sea benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate , Methanesulfonate, methylsulfate, 1,5-naphthalenedisulfonate, naphthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palm Acid salt, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonic acid Salt, trifluoroacetate and xinafoate.

It is also possible to form acid hemi-salts, such as hemisulfate and hemi-tartrate.

Those familiar with the art should understand that the above-mentioned salts include those in which the relative ion is optically active (for example, d-lactate) or racemic (for example, dl-tartrate).

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The pharmaceutically acceptable salt of the compound of formula (I) can be prepared by one or more of the following three methods: (i) By reacting the compound of formula (I) with the desired acid; (ii) Use the desired acid to remove the acid labile protecting group from the appropriate precursor of the compound of formula (I); or (iii) By converting a salt of the compound of formula (I) into another salt by reacting with a suitable acid or by means of a suitable ion exchange column.

All three reactions are usually carried out in solution. The resulting salt can be precipitated and collected by filtration, or it can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can vary from complete ionization to almost no ionization.

The compound of formula (I) or its pharmaceutically acceptable salt can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules (for example, ethanol). When the solvent is water, the term "hydrate" is used. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be replaced by isotope (for example, D ₂ O, d ₆ -acetone, and d ₆ -DMSO).

The currently accepted classification system for organic hydrates defines separation sites, channels or metal ion coordination hydrates. See Polymorphism in Pharmaceutical Solids , KR Morris (Edited by HG Brittain, Marcel Dekker, 1995), which is cited by reference Incorporated into this article. Separation site hydrates are those in which water molecules are separated from each other by intercalating organic molecules without direct contact. In channel hydrates, water molecules are located in lattice channels where they are adjacent to other water molecules. In metal ion coordination hydrates, water molecules are bonded to metal ions.

When the solvent or water is tightly bound, the compound will have a well-defined stoichiometry independent of humidity. However, when the solvent or water binding is weak, such as in channel solvates and hygroscopic compounds, the water/solvent content will depend on humidity and drying conditions. Under these circumstances, non-stoichiometric measurements will be normal.

The scope of the present invention also includes multi-component complexes (except salts and solvates) of the compound of formula (I) or pharmaceutically acceptable salts thereof, wherein the drug and at least one other component are stoichiometrically or non-chemically The metered quantity exists. Such complexes include clathrate compounds (drug-host incorporated into the complex) and co-crystals. The latter is usually defined as a crystalline complex of neutral molecular components, which are held together by non-covalent interactions, but can also be a complex of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, recrystallization from solvents, or physical grinding of the components together, see Chem Commun, 17 , 1889-1896, O. Almarsson and MJ Zaworotko (2004), which are incorporated herein by reference middle. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, Haleblian (August 1975), which is incorporated herein by reference.

The compound of the present invention may exist in a continuous solid state ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or liquid depending on the temperature. Generally, these materials do not produce characteristic X-ray diffraction patterns, and when they exhibit solid properties, they are more expounded as liquids in form. Upon heating, a change in properties from solid to liquid occurs, which is characterized by a change in state, usually a secondary change ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular and orderly internal structure at the molecular level and produces a characteristic X-ray diffraction pattern that defines peaks. When heated sufficiently, these materials will also exhibit a liquid form, but the change from solid to liquid is characterized by a phase change, usually a first-order change ("melting point").

The term "2theta" or "2θ" refers to the PXRD peak position (in degrees) along the x-axis. The typical error associated with the PXRD peak position is up to +/- 0.2° 2θ (USP-941).

The compound of the present invention can also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is the intermediate state between the true crystalline state and the true liquid state (melt or solution). The mesogenic phenomenon caused by temperature changes is described as "thermotropic liquid crystal" and the mesogenic phenomenon caused by the addition of a second component (such as water or another solvent) is described as "lyotropic liquid crystal". The compound with the possibility of forming a lyotropic mesophase is described as "amphiphilic" and is composed of an ionic polar head group (such as -COO ^- Na ⁺ , -COO ^- K ⁺ or -SO ₃ ^- Na ⁺ ) or non-ionic The molecular composition of a polar head group (for example -N ^- N ⁺ (CH ₃ ) _{3 ).} For more information, see Crystals and the Polarizing Microscope , NH Hartshorne and A. Stuart, 4th edition (Edward Arnold, 1970), which is incorporated herein by reference.

The compounds of the invention can be administered as prodrugs. Therefore, some derivatives of the compound of formula (I) may themselves have little or no pharmacological activity, but can be converted into the compound of formula (I) with desired activity by, for example, hydrolysis and dissociation when administered to the body or on the body. These derivatives are called "prodrugs". For additional information on the use of prodrugs, please refer to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (EB Roche Editor, American Pharmaceutical Association).

Prodrugs can be prepared, for example, by replacing the appropriate functional groups present in the compound of formula (I) with certain parts known to those skilled in the art as the "prodrugs", such as, for example, "Design of Prodrugs" , Explained in H Bundgaard (Elsevier, 1985).

Examples of prodrugs include phosphate prodrugs, such as dihydrogen phosphate or dialkyl (e.g., di-tertiary butyl) ester prodrugs. Other examples of substitution groups and examples of other prodrug types according to the above examples can be found in the aforementioned references.

The scope of the present invention also includes the metabolites of the compound of formula (I), in other words, the compound formed in the living body when the drug is administered. In the case where the compound of formula (I) according to Example E19 contains a morpholino moiety, examples of metabolites of the invention include hydroxyethylamine of formula (Ib) and amine of formula (Ic), as shown below.

M1                                          M2The following compounds M1 and M2 (metabolites of the compound of Example 1) illustrate this aspect of the present invention and are particularly interesting.

M1 M2

Examples of other metabolites of the present invention include: (i) hydroxymethyl derivatives (-CH ₃ → -CH ₂ OH); (ii) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative ( -(C ₁ -C ₆ )alkoxy→ -OH); and (iii) when the compound of formula (I) contains a phenyl moiety, its phenol derivative (-Ph→-PhOH).

Formula (I) contains an asymmetric cyclopropindazolyl moiety and is defined in a stereospecific manner (such as "4aS, 5aR" stereoisomers).

。Those familiar with the art should understand that one or more substituents in formula (I) can introduce one or more other asymmetric centers. An example of this other asymmetric center is the asymmetric carbon atom of the compound of formula (Ia) or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt of Example E14, which is hereinafter The representative figure of formula (Ia) is marked by an asterisk (*):

.

The compound of the present invention containing the one or more other asymmetric centers may exist in the form of two or more stereoisomers; the scope of the present invention includes all such stereoisomers (including epimers) of the compound of the present invention Body) and a mixture of two or more of them.

Conventional techniques for the preparation/separation of individual enantiomers include parallel synthesis from suitable optically pure precursors or resolution of racemates (or salts or derivatization) using (e.g.) counterpart high pressure liquid chromatography (HPLC) Racemate).

Alternatively, the racemate (or racemic precursor) can be combined with a suitable optically active compound (e.g. alcohol) or with a base or acid (e.g. 1-phenyl) in the case where the compound of formula (I) contains an acidic or basic moiety. Ethylamine or tartaric acid) reaction. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers can be converted into the corresponding pure enantiomers in a manner well known to those skilled in the art. Construct.

The anti-palm compound (and its anti-palm precursor) of the present invention can be chromatographed, usually HPLC is used on an asymmetric resin from 0 to 50% by volume, usually 2% to 20% of isopropanol and 0 to A mobile phase consisting of 5 vol% alkylamine, usually 0.1% diethylamine hydrocarbon, and usually heptane or hexane obtains an enantiomerically enriched form. The eluate was concentrated to obtain an enriched mixture.

Contrastive chromatography using subcritical and supercritical fluids can be used. The method of palmar chromatography that can be used in some embodiments of the present invention is well known; for example, see Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns) , pp. 223-249 and references cited therein.

Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art; for example, see "Stereochemistry of Organic Compounds", E. L. Eliel and S. H. Wilen (Wiley, New York, 1994.

In the case where structural isomers can be transformed into each other through low-energy barriers, tautomerism ("tautomerism") and conformational isomerism can occur.

;

The tautomerism in the compound of formula (I) can take the form of proton tautomerism, as illustrated below for the benzimidazole group in general formula (I) and specific example 1:

;

Those familiar with this technology should understand that proton tautomerism can also occur on the pyrazole ring in the compound of formula (I).

Although the compound of formula (I) is drawn in the form of a single tautomer for the sake of simplicity, all possible tautomeric forms and mixtures thereof are included in the scope of the present invention.

Configurational isomerism is a form of stereoisomerism in which compound isomers can only be converted into each other by rotating around a single bond. These isomers are generally called conformational isomers (conformational isomers or conformers) and specifically rotamers. "Rotameric mixture (or mixture of rotamer)" describes a compound that exists as a mixture of more than one possible configuration isomer. Although the compound of formula (I) is drawn in a single configuration for simplicity, all possible configuration isomers and mixtures thereof are included in the scope of the present invention.

The scope of the present invention includes all crystalline forms of the compounds of the present invention, including racemates and racemic mixtures (aggregates) thereof. Stereoisomeric aggregates can also be separated by the conventional techniques just described above.

The scope of the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the present invention, in which one or more atoms are replaced by atoms having the same atomic number but having an atomic weight or mass number different from the dominant atomic weight or mass number in nature .

Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen (e.g. ² H and ³ H), carbon (e.g. ¹¹ C, ¹³ C, and ¹⁴ C), fluorine (e.g. ¹⁸ F), chlorine (e.g. ³⁶ Cl), iodine (e.g., ¹²³ I and ¹²⁵ I), nitrogen (e.g., ¹³ N and ^15N ), oxygen (e.g., ¹⁵ O, ¹⁷ O, and ¹⁸ O).

Certain isotopically-labeled compounds of the present invention (for example, those incorporating radioisotopes) can be used for drug and/or substrate tissue distribution studies. The radioisotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are especially useful for this purpose because they are easy to incorporate and easy to detect. Substitution with heavier isotopes (such as deuterium (D), ie ² H) can provide certain therapeutic advantages due to stronger metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore in some cases Better. The use of positron emitting isotopes (such as ¹¹ C, ¹⁵ O, and ¹³ N) for substitution can be used to test the occupancy of the host receptor in a positron emission tomography (PET) study.

The isotopically-labeled compound of formula (I) can usually be replaced by an appropriate isotope-labeled reagent by a conventional technique known to those skilled in the art or by a method similar to that described in the accompanying examples and preparations. To prepare.

Those also within the scope of the present invention are the intermediate compounds, all salts, solvates and complexes thereof, and all solvates and complexes of their salts as defined previously for the compound of formula (I) as defined below. The present invention includes all polymorphs of the aforementioned substances and their crystal habits.

In preparing the compound of formula (I) of the present invention, those skilled in the art can routinely select intermediate forms that provide the best combination of features for this purpose. These characteristics include the melting point, solubility, processability and yield of the intermediate form, and the ease with which the product can be purified or separated.

The compounds of the present invention can be prepared by any method known in the art for preparing compounds of similar structure. In particular, the compounds of the present invention can be prepared by referring to the procedures described in the following reaction diagrams or by the specific methods described in the examples or by any of the similar methods.

Those familiar with the art should understand that the experimental conditions set forth in the following schemes are illustrative and suitable conditions for carrying out the displayed transformations, and it may be necessary or desirable to change the precise conditions used for the preparation of the compound of formula (I). It should be further understood that it may be necessary or desirable to perform the transformations in a different order than those set forth in the schemes or modify one or more of the transformations to provide the desired compounds of the invention.

The compound of the present invention contains two or more stereocenters, wherein the stereochemical symbol is (R) or (S). Those familiar with this technology should understand that all synthetic transformations can be performed for any enantiomerically enriched or racemic compound, and the desired resolution can be resolved at any synthesis point using well-known methods described herein and/or known in the industry. Stereoisomers.

In addition, those skilled in the art should understand that it may be necessary or desirable to protect one or more sensitive groups at any stage of the synthesis of the compounds of the present invention to prevent undesired side reactions. In particular, it may be necessary or desirable to protect the hydroxyl group, carboxyl group, and/or amine group. The protecting groups used to prepare the compounds of the present invention can be used in customary ways; for example, see the description in "Greene's Protective Groups in Organic Synthesis", Theodora W Greene and Peter GM Wuts, Fifth Edition (John Wiley and Sons, 2014) (which is described in The reference is incorporated herein) and in particular chapters 2, 5 and 7, respectively, the document also describes methods for removing these groups.

In the following general manufacturing process and unless otherwise stated: ● R ¹ to R ⁶ are as previously defined for the compound of formula (I); ● R is an alkyl group (for example, ethyl), or in the case of formulas 3 and 4 , Two Rs can form a cyclic acetal together with the oxygen atom to which they are connected; ● PG is a suitable amine protecting group, such as silyl ether (such as SEM), alkoxycarbonyl (such as BOC), acetyl ( Ac), benzyl (such as PMB) or dihydropyran (DHP) protecting group; and X is F or Cl.

The substituted pyrazole of Formula 11 can be prepared as shown in Reaction Figure 1.

可藉由伯奇還原(Birch reduction)(Mander, L. N.Comprehensive Organic Synthesis ；Trost, B. M.及Fleming, I.編輯；Pergamon: Oxford,1991 ，第8卷，pp. 489-521)使用鹼金屬(例如Li或Na)在低於-30℃之溫度下於液氨中來將化合物1 (3-甲氧基甲苯)還原成相應1,4-二烯化合物2。 Response Figure 1

Birch reduction may be by (Birch reduction) (Mander, LN Comprehensive Organic Synthesis; Trost, BM and Fleming, I. Editor; Pergamon:. Oxford, 1991, Vol. 8, pp 489-521) using an alkali metal (e.g. Li Or Na) The compound 1 (3-methoxytoluene) is reduced to the corresponding 1,4-diene compound 2 in liquid ammonia at a temperature below -30°C.

Can be used under catalytic acid conditions (e.g. using pTSA or CSA) in the presence of an alkyl primary alcohol (e.g. MeOH or EtOH) or glycol (e.g. ethylene glycol) with or without solvents (e.g. DCM or other aprotic solvents). Continue to prepare the olefinic acetal of formula 3 from 1,4-diene compound 2 at a temperature between 0-100°C (for example, 0-25°C).

Can be added via dihalocarbene or Simmons-Smith cyclopropanation (Charette, AB; Beauchemin, A. Simmons-Smith Cyclopropanation Reaction. Org. React. 2001 , 58 , p 1-415) Continue to convert the olefin of formula 3 into cyclopropane of formula 4.

The acetal of formula 4 can be deprotected in a mixture of water and solvent (for example THF) under acidic conditions (for example, using HCl, H ₂ SO _{4 or an organic acid (for example, pTSA)) to obtain the ketone of formula 5.}

The diketone of formula 6 can be prepared by reacting the ketone of formula 5 with the following: i) Dialkyl oxalate and 1-3 equivalents of strong base (such as LDA, LiHMDS or KOtBu) in a polar aprotic solvent (E.g. THF) at -78°C to 25°C; or ii) alkoxide in the corresponding alcohol solvent (e.g. EtONa in ethanol) at a temperature between 0°C and reflux.

Using hydrazine or hydrazine hydrate to condense the diketone of formula 6 in a protic solvent (such as MeOH or EtOH) at 25° C. to reflux can provide the pyrazole of formula 7. Hydrazine salts (such as HCl salts) and corresponding molar equivalents of inorganic (such as K ₂ CO ₃ ) or organic (such as Et3N or iPr ₂ NEt) bases can also be used.

SEM-Cl, DHP or another suitable protecting group can be used to protect the pyrazole of formula 7 to provide the pyrazole of formula 8, which can be resolved by supercritical fluid chromatography using a counter-solid phase to provide formula 9 The corresponding enantiomers.

LAH can be used to reduce the ester of formula 9 to the alcohol of formula 10 in an aprotic solvent (such as THF) at a temperature between 0°C and reflux.

The alcohol of formula 10 can be oxidized to the aldehyde of formula 11 by: i) using _{reagents such as PCC, PDC or MnO 2} in an aprotic solvent; or ii) by catalysis, for example by using TEMPO/bleach And TPAP/NMO (Caron, S., Dugger, RW, Gut Ruggeri, S., Ragan, JA, Brown Ripin, DH, Chem. Rev. 2006, 106, 2943-2989) or Swern oxidation conditions.

The compound of formula (I) can be prepared as shown in Reaction Figure 2, wherein R is H or PG.

可藉由以下方式對式12之4-硝基苯胺實施醯基化以提供式13之醯胺：利用羧酸且使用標準醯胺偶合試劑(例如EDCI、HATU、HBTU或T3P)；或與替代醯基化劑(例如醯氯或醯基咪唑)在介於0℃與回流之間之溫度下於溶劑(例如DCM或DMF)中在有機鹼(例如Et₃ N)存在下進行反應。 Response Chart 2

The 4-nitroaniline of formula 12 can be acylated to provide the amide of formula 13 by the following methods: using carboxylic acid and using standard amide coupling reagents (such as EDCI, HATU, HBTU or T3P); or alternatively The acylating agent (e.g., chloride or imidazole) is reacted in a solvent (e.g. DCM or DMF) at a temperature between 0°C and reflux in the presence of an organic base (e.g. Et ₃ N).

Alkylating agents (e.g. alkyl halides or toluenesulfonates) can be used to alkylate the amides of formula 13 in the presence of a base (e.g. KOtBu or LiHMDS) in a polar aprotic solvent (e.g. DMF or THF) To provide the amide of formula 14.

It can be achieved by substituting X in the compound of formula 14 with a nitrogen nucleophile (such as ammonia or benzylamine or substituted benzylamine) in a pure state or in a solvent (such as DMF or THF) at 25°C to 100°C Preparation of nitroaniline of formula 15.

Pd catalyst can be used under hydrogenation conditions (for example, 10% Pd/C under 1-3 atm H ₂ ), and reduction in alcohol solvent (for example, MeOH or EtOH) at a temperature between 20°C and 60°C The nitroaniline of formula 15 (with deprotection as necessary) to provide the o-diamine of formula 16. Alternatively, when R=H, the nitro group can be reduced by using a metal (such as Zn or Fe) in AcOH at a temperature between 20-100°C.

The aldehyde of formula 11 and oxidizing agent (such as Na ₂ S ₂ O ₅ ) can be used to condense the formula 16 in a polar solvent (such as DMF containing 2-5 equivalents of DMSO) at a temperature between 90°C and 150°C. Diamine to provide the benzimidazole of formula 17. Alternatively, _{the compounds of formula 16 and 11 can be condensed in the presence of NaHSO 3} aqueous solution and EtOH or other alcohol solvents at 60° C. to reflux.

The protective group in the compound of formula 17 can be removed under conditions well known to those skilled in the art to provide the corresponding compound of formula (I). For example, when PG = SEM, the protective group can be removed by TFA used in DCM, and Et ₃ SiH can be added as appropriate.

The compound of formula (I) can also be prepared from the 3-nitroaniline of formula 18 according to the reaction scheme 3 by the process directly corresponding to the process illustrated in reaction scheme 2.

亦可根據反應圖4來合成式(I)化合物，其中R係H或PG。 Response Figure 3

The compound of formula (I) can also be synthesized according to reaction diagram 4, wherein R is H or PG.

式(I) 可使用適當保護基團(例如BOC或Ac)對式12之4-硝基苯胺實施N 保護以提供式19化合物，繼而可使用烷基鹵化物實施N -烷基化(如上文在反應圖2中針對式14化合物之製備所闡述)以提供式20化合物。 Response Figure 4

Formula (I) can use a suitable protecting group (such as BOC or Ac) to implement N- protection of 4-nitroaniline of formula 12 to provide a compound of formula 19, and then can use alkyl halide to implement N -alkylation (as above The preparation of the compound of formula 14 is illustrated in the reaction diagram 2) to provide the compound of formula 20.

The compound of formula 20 can be substituted under aromatic nucleophilic substitution conditions to obtain the compound of formula 21; and then, for example, reduction can be performed under the conditions described above for the preparation of the compound of formula 16 in Reaction Figure 2 to obtain the compound of formula 22 Diamine; and finally the aldehyde-condensed diamine of formula 11 is used to provide the orthogonally protected compound of formula 23.

The aniline protecting group of the compound of formula 23 can be selectively deprotected to provide the aniline of formula 24 by the following methods: reacting with ZnBr ₂ or TMSOTf (PG = BOC) in a non-polar solvent (such as DCM); or Use an aqueous solution of NaOH or KOH in MeOH or EtOH to perform alkaline hydrolysis (PG = Ac) under reflux.

The aniline of formula 24 can be acylated under the conditions described above for the preparation of benzimidazole of formula 17 in Reaction Figure 2, and then under conditions well known to those skilled in the art (for example, in Reaction Figure 2 The benzimidazole is deprotected as described for the preparation of formula (I) to provide the compound of formula (I).

The compound of formula (I) can also be synthesized according to reaction diagram 5.

可使用式11之醛在反應圖2中針對式17化合物之製備所闡述之條件下縮合式25之1-溴-3,4-二胺基苯以提供式26之苯并咪唑，繼而可藉由與SEM-Cl在介於-78℃與60℃之間之溫度下於非質子溶劑(例如THF或DMF)中使用鹼(例如NaH、KOtBu或LiHMDS)進行反應來實施保護以提供式27a及27b之區域異構體混合物。可藉由習用技術自其分離式27b化合物。 Response Figure 5

The aldehyde of formula 11 can be used to condense the 1-bromo-3,4-diaminobenzene of formula 25 under the conditions described for the preparation of the compound of formula 17 in Reaction Figure 2 to provide the benzimidazole of formula 26, which can then be used The protection is implemented by reacting with SEM-Cl at a temperature between -78°C and 60°C in an aprotic solvent (such as THF or DMF) using a base (such as NaH, KOtBu or LiHMDS) to provide formula 27a and 27b is a mixture of regioisomers. The compound of formula 27b can be isolated therefrom by conventional techniques.

Although referring to Equation 27b to illustrate subsequent transformations, those who are familiar with this technique should understand: i. The mixture of regioisomers of formulas 27a and 27b can be finally used to prepare compounds of formula (I) (thereby preparing the corresponding pairs of regioisomers of formulas 29, 30 and 31); and ii. Regioisomers of compounds of formula 29, 30 or 31 can also be separated by conventional techniques and finally used to prepare compounds of formula (I).

The transition metal-catalyzed cross-coupling (also called Buchwald/Hartwig coupling (Buchwald/Hartwig coupling)) of a compound of formula 27b and a protected amine derivative (such as t-butyl carbamate) can provide The protected aniline of formula 28. The cross-coupling reaction can be catalyzed by Pd or Cu metal and appropriate ligands and uses a variety of bases (including Cs ₂ CO ₃ , LiHMDS, NaOtBu and KOtBu) at a temperature between 20°C and 120°C in a solvent (such as Toluene, tertiary amyl alcohol or 1,4-dioxane).

The protected aniline of formula 28 can be alkylated as described for the preparation of the compound of formula 14 in Reaction Figure 2 to provide the compound of formula 29. The following steps can then be carried out under customary conditions (for example, as described for the preparation of compounds of formulas 24, 17 and (I) in Reaction Figure 4, respectively): deprotection to provide the compound of formula 30, and acylation to provide the formula 31 The compound is finally deprotected to provide a compound of formula (I).

The compound of formula (I) can also be synthesized according to reaction diagram 6.

可在反應圖5中針對式30化合物之製備所闡述之條件下對式28化合物實施去保護以提供式32之苯胺，可在反應圖2中針對式17之苯并咪唑之製備所闡述之條件下實施醯基化以提供式33之醯胺。 Response Figure 6

The compound of formula 28 can be deprotected under the conditions described for the preparation of the compound of formula 30 in Reaction Figure 5 to provide the aniline of formula 32, and the conditions described for the preparation of the benzimidazole of Formula 17 in Reaction Figure 2 can be deprotected Next, acylation is performed to provide the amide of formula 33.

Under customary conditions (for example, as described in the preparation of the compounds of formula 14 and (I), respectively, as in Reaction Figure 2), the amide of formula 33 can be N-alkylated to provide the compound of formula 31 and then deprotected To provide a compound of formula (I).

It is also possible to synthesize the compound of formula (I) in which ^{R 4 is a morpholino substituent according to Reaction Figure 7.}

可藉由使用乙醯氯或乙酸酐以純淨狀態或於非質子溶劑(例如DCM)中使用有機鹼(例如Et₃ N)在介於-20℃與60℃之間之溫度下對式30之苯胺實施醯基化以提供式34之N -乙醯基化合物。 Response Figure 7

It can be achieved by using acetyl chloride or acetic anhydride in a pure state or using an organic base (e.g. Et ₃ N) in an aprotic solvent (e.g. DCM) at a temperature between -20°C and 60°C. The aniline is acylated to provide the N -acetyl compound of formula 34.

The compound of formula 34 can be treated with a strong base (such as LDA) in an aprotic solvent (such as THF), followed by chlorination with a reagent such as benzenesulfonyl chloride to provide the α-chloroamide of formula 35.

Appropriate morpholine can be used in an aprotic solvent (such as DMF or MeCN) in the presence of a base (such as K ₂ CO ₃ or Na ₂ CO ₃ ) and by adding NaI to treat the amide of formula 35 to provide a compound of formula 31, The deprotection can then be performed under customary conditions (such as those described for the preparation of the compound of formula (I) in Reaction Figure 2) to provide the compound of formula (I).

The compound of formula (I) can be converted into an alternative compound of formula (I) by functional group interconversion known to those skilled in the art. For example, when R ⁵ or R ⁶ is a halogen (such as Br or Cl), synthetic techniques (such as coupling reactions mediated by transition metals, including Suzuki and Buchwald/Hartwig) can be used. Cross-coupling, cyanidation, and boronization) to achieve additional transformations to manipulate substitution at these positions.

The compounds of formula 1, 12, 18 and 25 can be obtained from commercial sources, prepared by methods similar to literature methods, or by methods described in the following experimental chapters well known to those skilled in the art or their variations To get.

All new processes for preparing the compound of formula (I) or its pharmaceutically acceptable salt and the corresponding new intermediates used therein form other aspects of the present invention.

The compound of the present invention intended for medical use may be administered in amorphous or crystalline form or may exist in a continuous solid state ranging from completely amorphous to completely crystalline. These compounds can be obtained, for example, in the form of solid plugs, powders or films by using precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radio frequency drying can be used for this purpose.

The compound of the present invention can be administered by any suitable route in the form of a pharmaceutical composition suitable for this route and in a dose effective for the intended treatment. Generally, it will be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of excipients depends to a large extent on factors such as the following: the mode of administration, the effect of the excipients on solubility and stability, and the nature of the dosage form.

The administration modes of the compounds of the present invention include oral, parenteral, topical, rectal, vaginal, ocular and ear administration.

Oral administration may involve swallowing so that the compound of the invention enters the gastrointestinal tract, or buccal or sublingual administration so that the compound enters the blood stream directly from the oral cavity.

Parenteral administration may involve injection of the compound of the present invention into the blood stream, muscle or internal organs, where the injection may be intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, Intramuscular or subcutaneous injection. Parenteral administration can use needle (including micro-needle) syringes, needle-free syringes and infusion techniques.

Partial administration is better and includes: 　● Apply to skin, nails, hair, claws, hooves, mucous membranes; 　● dermal or transdermal injection; 　● Administer intranasally or by inhalation; 　● Rectal or vaginal administration; and 　● Directly in the eyes or ears.

The term "transdermal administration" refers to the spread of the compound of the present invention through the barriers of the skin, nails, hair, claws or hoofs by topical administration or application of other compositions. Transdermal delivery includes delivery through any part of the skin, nails, hair, claws, or hoof, and absorption or penetration through the remaining part.

Local administration of the compound of the present invention allows the compound to be distributed to the skin and surrounding tissues restrictively, or the compound of the present invention can be exposed systemically when the compound is removed from the treatment area from the blood stream. Preferably, topical administration of the compound of the present invention allows the compound to be restricted to the skin and surrounding tissues. In the case of systemic exposure of the compound of the present invention, the compound is preferably rapidly metabolized, thereby minimizing the systemic exposure of the compound of the present invention. Minimizing systemic exposure can reduce undesirable biological effects (ie, side effects).

In another aspect, the invention provides a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable excipient.

The pharmaceutical composition suitable for delivering the compound of the present invention and the preparation method thereof will be easily understood by those familiar with the art. Such compositions and preparation methods can be found in, for example, "Remington's Pharmaceutical Sciences", 19th edition (Mack Publishing Company, 1995).

The pharmaceutical composition is usually prepared by mixing the compound of the present invention and one or more excipients. Excipients include materials such as the following: carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, buffers, stabilizers, surfactants, Wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids, coloring agents, sweeteners, flavoring agents, flavoring agents and the like. The solvent may include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and mixtures thereof. The excipients are selected to facilitate the manufacture or application of the pharmaceutical composition.

The pharmaceutical composition can be prepared by conventional dissolution and mixing. For example, the compound of the present invention can be dissolved in a solvent in the presence of one or more of the above-mentioned excipients. The dissolution rate of poorly water-soluble compounds can be enhanced by using spray-dried dispersions, such as Takeuchi, H. et al., "Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent Deposition method and disintegrants" are described in J. Pharm. Pharmacol ., 39, 769-773 (1987) and US2002/009494, which are incorporated herein by reference.

Solid dosage forms for oral administration of the compound of the present invention include, for example, tablets, hard or soft capsules, lozenges, granules or powders, each of which contains at least one compound of the present invention. In these solid dosage forms, the compound of the present invention is usually combined with one or more pharmaceutically acceptable excipients. Solid dosage forms (such as tablets and capsules) for oral administration can be prepared by enteric coating.

Liquid dosage forms for oral administration of the compounds of the present invention include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs that contain inert diluents (such as water) commonly used in the industry. These compositions may also include excipients, such as wetting agents, emulsifiers, suspending agents, flavoring agents (such as sweetening agents) and/or perfuming agents.

The parenteral formulations of the compounds of the present invention are usually aqueous solutions containing excipients such as salts, carbohydrates and buffers (preferably buffered to pH 3-9). The formulations for parenteral administration may also be in sterile non-aqueous solution or dried (for example, lyophilized) form, which is intended to be administered after reconstitution with a suitable vehicle (for example, sterile, pyrogen-free water).

Pharmaceutical compositions for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants, and patches. If necessary, the compound of the present invention can be mixed with a pharmaceutically acceptable topical carrier and any preservative or buffer under aseptic conditions. Volatile compounds may need to be mixed with formulations or packaging materials to ensure proper dose delivery. Compounds of the present invention that have poor skin permeability may require one or more penetration enhancers, while compounds that are rapidly absorbed through the skin may need to be formulated using absorption delaying agents or barriers.

The term "pharmaceutically acceptable topical carrier" refers to a carrier medium suitable for topical application and suitably delivering an effective amount of the compound of the present invention, such as an inert liquid or cream vehicle capable of suspending or dissolving the compound. Those familiar with this technology should understand that this term also covers carrier materials approved for topical cosmetics.

The term "penetration enhancer" refers to increasing the permeability of the skin, nails, hair, claws or hoof to the compound of the present invention to increase the rate and extent of the compound's permeation. The enhanced penetration can be observed, for example, by using a diffusion cell device to measure the rate at which the drug diffuses through the skin, nails, hair, claws, or hooves of animals or humans. The diffusion cell is described by Merri et al. in Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162.

In addition to the compounds of the present invention, ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants and patches for topical administration may also contain one or more medicines. Acceptable excipients, such as animal or vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, polysiloxane, bentonite, silicic acid, talc, zinc oxide , Preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, tackifiers, fragrances, sunscreens, antioxidants, gelling agents, stabilizers, surfactants, softeners, Coloring agent, preservative, buffer, penetration enhancer. These excipients should not interfere with the effectiveness of the biological activity of the active agent and should not be harmful to epithelial cells or their functions.

Transdermal patch can be used to achieve transdermal administration. Transdermal patches can be of the "reservoir and porous membrane" type or use a "matrix system".

The solubility of the compounds of the present invention used in the preparation of pharmaceutical compositions can be enhanced by means of appropriate formulation techniques (for example, the inclusion of solubilizers).

The pharmaceutical composition can be formulated for immediate release and/or release in an improved manner. Conveniently, the compounds of the invention are formulated for immediate release

Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release. Therefore, the compound of the present invention can be formulated as a solid, semi-solid or thixotropic liquid for administration in the form of an implanted reservoir, thereby releasing the active compound in an improved manner. Examples of such formulations include poly( dl -lactic-co-glycol) acid (PGLA) microspheres.

The compound of the present invention can be used in combination with soluble macromolecules (such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers) to improve its solubility and dissolution rate when used in any of the above-mentioned administration methods , Taste masking, bioavailability and/or stability.

For administration to human patients, the total daily dose of the compound of the present invention is usually in the range of 1 mg to 10 g (e.g. 60 mg to 6 g, e.g. 100 mg to 1.5 g), depending on the mode of administration and efficacy. For example, administration may require a total daily dose of 200 mg to 1 g (e.g., 250 mg to 750 mg). The total daily dose may be administered in single or divided doses and may be outside the typical range given herein at the discretion of the physician. These dosages are based on a general human subject weighing about 60 kg to 70 kg. The physician will be able to easily determine the dosage for individuals whose body weight is outside this range (such as infants and young children and the elderly).

As described above, the compounds of the present invention are useful because they exhibit pharmacological activity (ie, ITK inhibition) in animals. More specifically, the compounds of the present invention are useful for treating the indications of ITK inhibitors.

Preferably, the animal is a mammal, more preferably a human.

Preferably, the compounds of the invention also inhibit TRKA.

In another aspect of the present invention, there is provided a compound of the present invention for use as a medicament.

In another aspect of the present invention, there is provided a compound of the present invention for the treatment of indications of ITK inhibitors.

In another aspect of the present invention, there is provided the use of the compound of the present invention to prepare a medicament for the treatment of indications of ITK inhibitors.

In another aspect of the present invention, a method for treating an indication of an ITK inhibitor in an animal (preferably a mammal, more preferably a human) is provided, which comprises administering to the animal a therapeutically effective amount of the compound of the present invention.

The diseases or conditions that ITK inhibitors are suitable for include inflammatory, autoimmune, skin, eye, respiratory, joint, cardiovascular and neuroinflammatory diseases. Those familiar with this technology should understand that a given disease, disorder or condition can belong to more than one of the above categories.

More specifically, the diseases or conditions that ITK inhibitors are suitable for include: ●Inflammatory diseases, such as allergic conjunctivitis, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis, microscopic Colitis (such as collagenous colitis or lymphocytic colitis), diversion colitis, Behcet's disease and indeterminate colitis), nephritis, retinitis, retinopathy, myositis, vasculitis , Sjogren's syndrome, Wegener's granulomatosis, arteritis, sclerosing cholangitis and eosinophilic globular esophagitis; ●　 Autoimmune disorders, such as lupus nephritis, autoimmune hepatitis, myasthenia gravis, Guillain-Barre syndrome and Graves' disease; ●　 Eye diseases or symptoms, including autoimmune eye disease, keratoconjunctivitis, vernal conjunctivitis, non-infectious uveitis (such as uveitis and lens-induced uveitis related to Behçet’s disease), Keratitis (such as herpetic keratitis and keratitis), corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, retinitis, retinopathy, Grave's eye disease (Grave's ophthalmopathy), Vogt-Koyanagi-Harada syndrome (Vogt-Koyanagi-Harada syndrome), keratoconjunctivitis sicca (dry eye), vesicles, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic Ophthalmia, allergic conjunctivitis and ocular vascular hyperplasia; ●　 Dermatological conditions, such as eczema (such as chronic and sweaty eczema), chronic itching, dermatitis (such as atopic dermatitis, irritant contact dermatitis, allergic contact dermatitis, occupational Dermatitis, perioral dermatitis, stasis dermatitis, nummular dermatitis, seborrheic dermatitis, dry dermatitis, eyelid dermatitis, diaper dermatitis and hand dermatitis), vitiligo, alopecia areata, Itching (e.g. chronic idiopathic itching), psoriasis (e.g. plaque psoriasis, guttate psoriasis, reverse psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, palmoplantar psoriasis, facial psoriasis, or erythroderma Psoriasis), scleroderma, pemphigus, dermatomyositis, neurodermatitis, skin redness, urticaria, cutaneous lupus erythematosus (e.g. acute cutaneous lupus, acute skin lupus), subacute skin lupus (subacute skin lupus) Acute lupus) and chronic skin lupus (disc lupus)), keloids, sunburn, hypertrophic scars, idiopathic thrombocytopenic thrombotic purpura (also known as immune thrombocytopenic purpura (ITP)), ichthyosis (E.g. ichthyosis vulgaris), epidermal hyperplasia, acne, lichen planus, lichen sclerosis, rosacea, epidermolysis bullosa, abrasions, keratosis pilaris, urticaria (e.g. chronic spontaneous urticaria, chronic characteristic Primary urticaria, chronic physical urticaria), molluscum contagiosum, Netherton syndrome, Vogt-Koyanagi-Harada syndrome, Sweet's syndrome , Pityriasis white, vulvovaginitis, Sutton's nevus/nevi, hypopigmentation after inflammation, age-related leukoplakia, chemical/drug-induced leukoplakia, palmoplantar pustulosis, pemphigoid and suppurative Hidradenitis; ● Respiratory symptoms, such as rhinitis (such as allergic and perennial rhinitis), rhinorrhea, nasal congestion, nasal inflammation, asthma (such as chronic asthma, intractable asthma, late-stage asthma, bronchial asthma, allergic asthma, endogenous asthma , Exogenous asthma and dusty asthma), chronic obstructive pulmonary disease (COPD), chronic and acute bronchoconstriction, chronic bronchitis, emphysema, chronic eosinophilic pneumonia, acute lung injury (ACI), adult respiratory distress Syndrome (ARDS), pulmonary vascular disease (PVD), pulmonary hypertension (PAH), bronchiectasis, sinusitis, pulmonary sarcoidosis and silicosis; ●　 Joint disorders, such as arthritis (such as osteoarthritis and psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, and gouty arthritis), spondyloarthropathy (such as reactive arthritis (also known as Leiter) Reiter's Syndrome and axial spondyloarthritis (including articular adhesive spondylitis), cartilage inflammation, bone degeneration, and Still's disease; ●　 Cardiovascular and metabolic disorders, such as diabetes (type 1 and type 2), diabetic neuropathy, cachexia and stomatitis diarrhea; and ● Nerve inflammatory disorders, such as lupus (such as CNS lupus, systemic lupus, and discoid lupus), diabetic neuropathy, and multiple sclerosis.

Allergic contact dermatitis (ACD) is a contact dermatitis characterized by an allergic reaction to contact materials. An example of ACD is urushiol-induced contact dermatitis (also known as poison sumac dermatitis or sumac dermatitis), which is found in various plants (including poisonous ivy, poisonous oak, poisonous sumac and Chinese sumac) Caused by urushiol oil. Other allergens that can induce ACD include chromium, gold and nickel.

Irritant contact dermatitis (ICD) can be divided into a form caused by chemical irritants and a form of contact dermatitis caused by physical irritants. Common chemical irritants include acids, alkalis, latex, oils, fragrances and preservatives in cosmetics, solvents and surfactants.

Occupational dermatitis is derived from ACD or ICD that is exposed to allergens or irritants in the work environment.

In addition, ITK inhibitors can be used to treat certain viral and bacterial infections, transplant rejection, septic shock, acute or chronic graft-versus-host disease, polymyalgia rheumatica, sarcoidosis, Addison's disease (Addison's disease) And Raynaud's syndrome.

In one embodiment, the disorder or condition to which the ITK inhibitor is adapted is a dermatological condition. In another embodiment, the dermatological condition to which the ITK inhibitor is adapted is dermatitis. In another embodiment, the dermatitis to which the ITK inhibitor is adapted is atopic dermatitis.

The compounds of the present invention can be used in combination with one or more other pharmacologically active compounds. These combinations may provide significant advantages including patient compliance, ease of administration, and synergistic activity.

In another aspect of the present invention, a combination of the compound of the present invention and another pharmacologically active compound or two or more other pharmacologically active compounds is provided.

In these combinations, the compound of the present invention and the other pharmacologically active compound may be administered simultaneously (for example, in a single dosage form, for example for topical administration with a composition, such as a cream or ointment), sequentially or separately.

One or more other therapeutic agents can be selected from any of the following agents or types of agents: ● Agents for the treatment of autoimmune and/or inflammatory disorders, such as sulfasalazine, mesalazine ), azathioprine, antibodies (e.g. infliximab, adalimumab, belimumab, tanezumab, ranibizumab Anti-(ranibizumab), bevacizumab, mepolizumab, certolizumab, natalizumab and vedolizumab) , 6-mercaptopurine, hydroxychloroquine, mofetil, sodium mycophenolate, leflunomide, rituxan, solumedrol, depomedrol , Non-steroidal anti-inflammatory drugs (NSAID) (such as aspirin, ibuprofen, celecoxib, valdecoxib, WBI-1001 and MRX-6) and cortical Steroids (such as betamethasone, dexamethasone and prednisone); ● Agents used to treat dermatological conditions, such as immunosuppressants (such as cyclosporin, other Tacrolimus and pimecrolimus), antibodies (e.g. infliximab, adalimumab, dupiluzumab, omalizumab, and Efalizumab), TNF inhibitors (e.g. etanercept), PDE4 inhibitors (e.g. crisaborole) and topical corticosteroids (e.g. fluocinonide), Mapracorat, hydrocortisone, desonide, alclometasone, triamcinolone and desoximetasone); ● Used Drugs for the treatment of respiratory conditions, such as oxymetazoline, rifampin, antihistamines (such as fexofenadine (fex ofenadine, loratidine, desloratidine, levocetirizine, methapyrilene, cetirizine), leukotriene receptors Antagonists (e.g. montelukast and zafirlukast), 5-lipoxygenase activated protein (FLAP) antagonists, muscarinic receptor antagonists (e.g. tiotropium bromide (tiotropium) ) And ipratropium), cromolyn, sodium nedocromil, corticosteroids (e.g. budesonide, fluticasone, mometasone, dexamethasone) dexamethasone), prednisolone, ciclesonide and beclomethasone), β-2 agonists (e.g. salmeterol, albuterol, salbutamol ( salbutamol), fenoterol and formoterol) and antibodies (such as omalizumab); ● Agents for the treatment of joint disorders, such as methotrexate, Azathioprine and NSAID (such as aspirin, ibuprofen, celecoxib, valdecoxib WBI-1001 and MRX-6); ● For treatment Drugs for cardiovascular and metabolic disorders, such as ursodeoxycholic acid, chloroquine, quinacrine, methylnorephrine, phenylephrine, methoxamine ), oxymetazoline, theophylline, PDE5 inhibitors (such as sildenafil, vardenafil and tadalafil), PDE4 inhibitors (such as Celiac Borrol, ibudilast, cilomilast, roflumilast and apremilast) and kinin B ₁ or B ₂ receptor antagonists; and ● Medicaments for the treatment of neuroinflammatory disorders, such as cyclophosphamide . One or more other therapeutic agents can also be selected from any of the following agents: ● JAK inhibitors, such as abrocitinib, baricitinib, brepocitinib, sedox Cerdulatinib, decernotinib, delgocitinib, fedratinib, filgotinib, gandotinib, igatinib (ilginatinib), itacitinib, lestatinib, momelotinib, oclacitinib, pacritinib, peficitinib , Ritlecitinib, ruxolitinib, tofacitinib, upadacitinib, ATI-502, BMS-986165, JTE052, PF-06826647, SNA- 152 and SHR-0302; ● Aryl hydrocarbon receptor agonists, such as tapinarof; ● IRAK4 inhibitors, such as PF-06650833; ● Vitamin D analogs, such as calcipotriene; ● Retinoic acid derivatives, such as alitretinoin; ● Liver X receptor (LXR) selective agonists, such as VTP-38543; ● H4 receptor antagonists, such as ZPL-389; ● NKI receptor antagonists Agents, such as aprepitant and tradipitant; ● CRTH2 receptor antagonists, such as fevipiprant and OC-459; ● chymosin inhibitors, such as SUN 13834; ● GATA-3 inhibitors, such as SB-011 and GR-MD-02; ● ROR inverse agonists, such as VTP-43742, ARN6039, TAK-828 and JTE-451; ● Immunomodulators, such as PF-06763809; and ● Inhibitors of SYK and BTK, including (but not limited to) R-348, fostamatinib, mastinib, mivavotinib, sperbrutinib, fenib Fenebrutinib, sedutinib, ibrutinib, entospleti nib) and tellutinib (tirabrutinib).

Within the scope of the present invention, two or more pharmaceutical compositions (at least one of which contains the compound of the present invention) can be conveniently combined into a kit form suitable for co-administration of the composition. Therefore, the kit of the present invention includes two or more separate pharmaceutical compositions (at least one of which contains the compound of the present invention) and a member for storing the compositions separately (for example, a container, a separate bottle, or a separate type). Foil package). Examples of this set are commonly used in blister packs such as tablets, capsules and the like. The kit of the present invention is particularly suitable for administering different dosage forms (for example, topical, oral, parenteral, etc.), for administering separate compositions at different dosage intervals, or for mutual titration of separate compositions. To aid compliance, the kit usually includes dosing instructions and may be provided with so-called memory aids.

In another aspect, the present invention provides a medicinal product (for example, in the form of a kit), which includes a compound of the present invention and one or more other therapeutically active agents as a combined preparation for simultaneous, separate or sequential use in the treatment of ITK inhibitors The indications.

It should be understood that all the treatments mentioned in this article include radical treatment, palliative treatment and preventive treatment.

The following abbreviations, definitions and analysis procedures can be mentioned in the non-limiting examples and preparations described below to illustrate the present invention and in the above reaction diagrams: ° 2θ is the degree 2-θ; AcOH is acetic acid; Ac ₂ O is ethyl Acid anhydride; APC-based allophycocyanin; aq.-based water-based; atm-based atmosphere; ATP-based trihydrate 5′-adenosine triphosphate disodium salt; BINAP-based (2,2′-bis(diphenylphosphino)-1,1 ′-Binaphthalene); Boc is the tertiary butoxycarbonyl group; BOC ₂ O is the BOC anhydride, that is, di-tertiary butyl dicarbonate; br is the broad peak; BTFFH is the fluorobis(tetramethylene) hexafluorophosphate Base) formamidine; BTK is Bruton's tyrosine kinase (Bruton's tyrosine kinase); ℃ is Celsius; CD ₃ OD is deuterated-methanol; CDCl ₃ is deuterated-chloroform; conc. is concentrated; CSA is camphor Sulfonic acid; δ is the chemical shift; d is the doublet; dd is the doublet of the doublet; ddd is the doublet of the doublet of the doublet; dt is the doublet of the triplet; DAST is the diethylaminosulfur trifluoride; DCM is the system Dichloromethane; DCE is 1,2-dichloroethane; Dess-Martin periodinane is triacetic acid 3-oxo-1,3-dihydro-1λ ⁵ ,2-benzene Iodoxolane-1,1,1-triyl ester; DHP-based dihydropyran; DMAP-based 4-dimethylaminopyridine; DMF-based N,N-dimethylformamide; DMSO-based Dimethyl sulfide; EDCI series 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; ee series enantiomeric excess; EDTA series ethylene diamine tetraacetic acid ; ESI-MS series electrospray ionization mass spectrometry; EtOAc series ethyl acetate; EtOH series ethanol; EtONa series sodium ethoxide; Et ₃ N series triethylamine; Et ₃ SiH series triethylsilane; g series grams; h series hours ; HATU series hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide; HBTU series six Fluorophosphate N,N,N',N' -tetramethyl- O- (1 H -benzotriazol-1-yl)uronium; HEPES series (4-(2-hydroxyethyl)-1-hexa Hydrogen pyrazine ethanesulfonic acid); HPLC system high pressure liquid chromatography; iPr ₂ NEt system N,N-diisopropylethylamine, also known as Hunig's base (Hunig's base); KOAc system potassium acetate; KOtBu is potassium tertiary butoxide; L is liter; LAH is lithium aluminum hydride; LCMS is liquid chromatography/mass spectrometry; LDA is lithium diisopropylamide; LiHMDS is lithium hexamethyldisilamide, also known as Lithium bis(trimethylsilyl)amide; m series multiplet; M series molar concentration; MeCN is acetonitrile; MeNH ₂ is methylamine; MeOH is methanol; MHz is MHz; min is minutes; mL is milliliter; mm is millimeter; mmol is millimolar; mol is mole; MS m/z is mass spectrum peak; MTBE is methyl tertiary butyl ether; n -BuLi is n-butyl lithium; NaHMDS is sodium bis(trimethylsilyl)amide; NaOtBu is sodium tertiary butoxide; NMP is N -methyl-2- Pyrrolidone; NMR system nuclear magnetic resonance; ORTEP system Oak Ridge Thermal Ellipsoid Plot; PCC system pyridinium chloride chromate; PDC system pyridinium dichromate; Pd ₂ (dba ₎₃ system ginseng ( Dibenzylideneacetone)dipalladium(0); Pd/C series palladium on carbon; Pd(dppf)Cl ₂ series 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) ; Pd(OAc) ₂ series palladium(II) acetate; Pd(OH) ₂ /C series carbon-supported palladium hydroxide(II); Pd(PPh ₃ ) ₄ series tetrakis(triphenylphosphine)palladium(0); PE Petroleum ether; PhCH ₃ toluene; PMB p -methoxybenzyl; p TSA monohydrate p-toluenesulfonic acid; PXRD powder X-ray diffraction; q quartet; Qphos 1,2,3, 4,5-Pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; RT is room temperature; s is singlet; sat. is saturated; SEM-Cl is 2-(trimethyl Silyl)ethoxymethyl chloride; SFC system supercritical fluid chromatography; SPhos system 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; SXRD system single crystal X-ray diffraction ; T is the triplet; tert -BuDavePhos is 2-di-tertiary butylphosphino-2'-(N,N-dimethylamino) biphenyl; t-BuOH is tert-butanol; TCEP is ginseng (2-Carboxyethyl)phosphine; TFA series trifluoroacetic acid; TFAA series trifluoroacetic anhydride; TGA series thermogravimetric analysis; THF series tetrahydrofuran; TMSCF ₃ series trifluoromethyltrimethylsilane; TMSOTf series trifluoromethanesulfonate Trimethylsilyl acid ester; T ₃ P series propyl phosphonic acid anhydride; Tris series ginseng (hydroxymethyl) aminomethane; µm series micrometer; v/v series volume to volume; w/v series volume to volume; Xantphos It is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; and ZnEt ₂ is diethyl zinc.

Unless otherwise stated, all reactions are run under a nitrogen atmosphere. When sodium hydride is used in the following procedures, the weight is corrected to reflect its application as a 60% suspension in mineral oil. RT (room temperature) usually means about 22°C (± 5°C). The term "concentration" refers to the process of removing volatile compounds (such as solvents) by using a rotary evaporator under reduced pressure.

^{The 1} H and ¹⁹ F nuclear NMR spectra are consistent with the proposed structure in all cases. ^{The characteristic δ of 1} H-NMR is relative to the residual solvent signal (for CDCl ₃ , δH = 7.27 ppm; for DMSO-d ₆ , δH = 2.50 ppm; for CD ₃ OD, δH = 3.30 ppm ; For DMF-d ₇ , δH = 8.03 ppm) is reported using the customary abbreviation of the main peak name. Those familiar with this technique should understand that tautomers can be recorded in NMR data and some exchangeable protons may not be visible. Likewise, those familiar with this technique should understand that mixtures of rotamers can be recorded in NMR data.

Use any ESI-MS to record mass spectra. Appropriately and unless stated otherwise, the m/z data provided are for the isotopes ¹⁹ F, ³⁵ Cl, ⁷⁹ Br and/or ⁸¹ Br and ¹²⁷ I.

In the case of using preparative TLC or silica gel chromatography, those skilled in the art should understand that any suitable solvent or combination of solvents can be used to purify the desired compound.

The compound names of the following preparations and examples are generated using ChemDraw Professional 18.0 (Perkin Elmer) according to IUPAC (International Union of Pure and Applied Chemistry).

實施25個平行批次之反應。向1-甲氧基-3-甲基苯(500 g, 4.09 mol)於t-BuOH (1.5 L)及THF (1 L)中之溶液中鼓入無水氨(1.4 kg, 82.2 mmol)，同時使反應液保持於-60℃與-50℃之間。然後向反應混合物中逐份添加鋰砂(62.5 g, 9.0 mol)，同時維持溫度介於-60℃與-50℃之間且將反應液攪拌2 h。將反應混合物緩慢升溫至約20℃且蒸發氨。向反應液中添加NH₄ Cl (500 g)及水(500 mL)。合併各批次，且分離有機層。使用EtOAc (5 L ×2)洗滌水層。然後使用鹽水(5 L)洗滌合併之有機層且乾燥(Na₂ SO₄ )有機層，並濃縮以提供標題化合物 (10.1 kg, 80%)。¹ H NMR (400 MHz, CDCl₃ ) δ 5.42 - 5.41 (m, 1H), 4.65 - 4.63 (m, 1H), 3.56 (s, 3H), 2.79 - 2.77 (m, 2H), 2.65 - 2.56 (m, 2H), 1.74 - 1.68 (m, 3H)。 preparation Preparation 1 : 1- Methoxy -5- Methylcyclohexyl -1,4- Diene

Perform 25 parallel batch reactions. Anhydrous ammonia (1.4 kg, 82.2 mmol) was bubbled into a solution of 1-methoxy-3-methylbenzene (500 g, 4.09 mol) in t-BuOH (1.5 L) and THF (1 L), while Keep the reaction solution between -60°C and -50°C. Then lithium sand (62.5 g, 9.0 mol) was added portion by portion to the reaction mixture while maintaining the temperature between -60°C and -50°C and stirring the reaction solution for 2 h. The reaction mixture was slowly warmed to about 20°C and ammonia was evaporated. Add NH to the reaction solution₄ Cl (500 g) and water (500 mL). The batches were combined, and the organic layer was separated. The aqueous layer was washed with EtOAc (5 L×2). Then use brine (5 L) to wash the combined organic layer and dry (Na₂ SO₄ ) Organic layer and concentrated to provideTitle compound (10.1 kg, 80%).¹ H NMR (400 MHz, CDCl₃ ) δ 5.42-5.41 (m, 1H), 4.65-4.63 (m, 1H), 3.56 (s, 3H), 2.79-2.77 (m, 2H), 2.65-2.56 (m, 2H), 1.74-1.68 (m , 3H).

實施6個平行批次之反應。在-10℃與0℃之間，向製備物1 (500 g, 4.03 mol)於DCM (4.0 L)中之溶液中添加單水合對甲苯磺酸(46.8 g, 201 mmol)及乙二醇(399 g, 6.04 mol)。將混合物在大約0℃下攪拌0.5 h。合併各反應批次並使用NaHCO₃ 飽和水溶液(5 L)、水(5 L, 2×)洗滌，乾燥(Na₂ SO₄ )，過濾並濃縮以提供標題化合物 (14.2 kg)。¹ H NMR (400 MHz, CDCl₃ ) δ 5.40-5.34 (m, 1H), 3.98-3.88 (m, 4H), 2.21-2.12 (m, 4H), 1.67 (d, 5H)。 Preparation 2 : 7 -methyl -1,4- dioxaspiro [4.5] dec -7- ene

Perform 6 parallel batch reactions. Between -10°C and 0°C, to a solution of Preparation 1 (500 g, 4.03 mol) in DCM (4.0 L) was added p-toluenesulfonic acid monohydrate (46.8 g, 201 mmol) and ethylene glycol ( 399 g, 6.04 mol). The mixture was stirred at approximately 0°C for 0.5 h. The reaction batches were combined and _{washed with saturated aqueous NaHCO 3} (5 L), water (5 L, 2×), dried (Na ₂ SO ₄ ), filtered and concentrated to provide the title compound (14.2 kg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.40-5.34 (m, 1H), 3.98-3.88 (m, 4H), 2.21-2.12 (m, 4H), 1.67 (d, 5H).

實施10個平行批次之反應。在0℃下冷卻ZnEt₂ (1.00 M, 5.14 L)於DCM (2.0 L)中之溶液，在0℃下向其中逐滴添加TFA (380 mL, 5.14 mol)。將混合物在0℃下攪拌30 min，然後在0℃下逐滴添加CH₂ I₂ (414 mL, 5.14 mol)。將混合物在0℃下攪拌30 min。逐滴添加製備物2 (396 g, 2.57 mol)，將溫度維持在0℃下且將所得混合物在0℃下攪拌30 min。將反應混合物傾倒至水(1 L)中且合併各批次。使用DCM (3 × 8 L)萃取合併之混合物。乾燥(Na₂ SO₄ )合併之有機相，過濾並濃縮以提供標題化合物 (3.0 kg)；¹ H NMR (400 MHz, CDCl₃ )δ 3.93 - 3.73 (m, 4H), 2.13 - 2.01 (m, 1H), 1.84 - 1.79 (m, 1H), 1.75 - 1.67 (m, 2H), 1.47 - 1.36 (m, 1H), 1.27 (m, 1H), 1.03 (s, 3H), 0.73 - 0.61 (m, 1H), 0.35 - 0.25 (m, 2H)。 Preparation 3 : 1- Methyl spiro [ Double ring [4.1.0] Heptane -3,2'-[1,3] Dioxolane ]

Perform 10 parallel batch reactions. Cool ZnEt at 0℃₂ (1.00 M, 5.14 L) in DCM (2.0 L), to which TFA (380 mL, 5.14 mol) was added dropwise at 0°C. The mixture was stirred at 0°C for 30 min, and then CH was added dropwise at 0°C₂ I₂ (414 mL, 5.14 mol). The mixture was stirred at 0°C for 30 min. Preparation 2 (396 g, 2.57 mol) was added dropwise, the temperature was maintained at 0°C and the resulting mixture was stirred at 0°C for 30 min. The reaction mixture was poured into water (1 L) and the batches were combined. The combined mixture was extracted with DCM (3×8 L). Dry (Na₂ SO₄ ) Combine the organic phase, filter and concentrate to provideTitle compound (3.0 kg);¹ H NMR (400 MHz, CDCl₃ )δ 3.93-3.73 (m, 4H), 2.13-2.01 (m, 1H), 1.84-1.79 (m, 1H), 1.75-1.67 (m, 2H), 1.47-1.36 (m, 1H), 1.27 (m, 1H) ), 1.03 (s, 3H), 0.73-0.61 (m, 1H), 0.35-0.25 (m, 2H).

實施14個平行批次之反應。使用pTSA·H₂ O (34.0 g, 178 mmol)處理製備物3 (300 g, 1.78 mol)於THF (1.5 L)及水(300 mL)中之溶液。將混合物在60℃下攪拌3 h且然後冷卻至室溫。合併14個批次並使用NaHCO₃ 飽和水溶液處理直至pH介於6-7之間為止。使用MTBE (3 × 8 L)萃取混合物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化殘餘物以提供標題化合物 (1.2 kg, 39%)。¹ H NMR (400 MHz, CDCl₃ ) δ 2.60 - 2.40 (m, 1H), 2.32 - 2.18 (m, 1H), 2.11 - 1.93 (m, 1H), 1.34 - 1.17 (m, 1H), 1.17 - 1.05 (m, 4H), 0.95 - 0.86 (m, 1H), 0.85 - 0.74 (m, 2H), 0.43 - 0.33 (m, 1H)。 Preparation 4 : 1- Methyl bicyclic [4.1.0] Heptane -3- ketone

Perform 14 parallel batch reactions. Use pTSA·H₂ A solution of Preparation 3 (300 g, 1.78 mol) in THF (1.5 L) and water (300 mL) was treated with O (34.0 g, 178 mmol). The mixture was stirred at 60°C for 3 h and then cooled to room temperature. Combine 14 batches and use NaHCO₃ Saturated aqueous solution treatment until the pH is between 6-7. The mixture was extracted with MTBE (3 × 8 L) and dried (Na₂ SO₄ ), filtered and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%) to provideTitle compound (1.2 kg, 39%).¹ H NMR (400 MHz, CDCl₃ ) δ 2.60-2.40 (m, 1H), 2.32-2.18 (m, 1H), 2.11-1.93 (m, 1H), 1.34-1.17 (m, 1H), 1.17-1.05 (m, 4H), 0.95-0.86 (m, 1H), 0.85-0.74 (m, 2H), 0.43-0.33 (m, 1H).

實施4個平行批次之反應。在0℃下，使用EtONa (126 g, 1.77 mol)處理製備物4 (200 g, 1.61 mol)於EtOH (1.0 L)中之溶液。在0℃下添加草酸二乙酯(259 g, 1.77 mol, 242 mL)且將混合物緩慢升溫至20℃並攪拌1 h。合併4個批次且將混合物傾倒至1N HCl (5 L)中並使用DCM (3 × 3 L)萃取。乾燥(Na₂ SO₄ )合併之有機萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-10%)純化殘餘物以提供標題化合物 (1.4 kg, 97%)。LC/MSm/z (M+H)⁺ = 225.0 Preparation 5 : 2-(6- methyl -4- Pendant oxybicyclic ring [4.1.0] Heptane -3- base )-2- Ethyl pendant oxyacetate

Perform 4 parallel batch reactions. A solution of Preparation 4 (200 g, 1.61 mol) in EtOH (1.0 L) was treated with EtONa (126 g, 1.77 mol) at 0°C. Diethyl oxalate (259 g, 1.77 mol, 242 mL) was added at 0°C and the mixture was slowly warmed to 20°C and stirred for 1 h. The 4 batches were combined and the mixture was poured into 1 N HCl (5 L) and extracted with DCM (3×3 L). Dry (Na₂ SO₄ ) The combined organic extracts are filtered and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-10%) to provideTitle compound (1.4 kg, 97%). LC/MSm/z (M+H)⁺ = 225.0

實施4個平行批次之反應。在0℃下，向製備物5 (350 g, 1.56 mol)於EtOH (1.5 L)中之溶液中添加水合肼(79.7 g, 1.56 mol)。將所得混合物在20℃下攪拌2 h。合併4個反應批次，向其中添加H₂ O (10 L)並使用DCM (3 × 8 L)萃取。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 5-33%)純化粗產物以提供標題化合物 (800 g, 58%)。¹ H NMR (400 MHz, DMSO-d₆ ) δ 13.70 - 12.78 (m, 1H), 4.25 - 4.20 (m, 2H), 3.14 - 3.07 (m, 1H), 2.89 - 2.82 (m, 2H), 2.68 - 2.62 (m, 1H), 1.27 (br s, 3H), 1.20 (br s, 3H), 1.04 - 1.00 (m, 1H), 0.31 - 0.29 (m, 1H), 0.08 - 0.02 (m, 1H)；LC/MSm/z (M+H)⁺ = 221.0。 Preparation 6 : 5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate

Perform 4 parallel batch reactions. At 0°C, to a solution of Preparation 5 (350 g, 1.56 mol) in EtOH (1.5 L) was added hydrazine hydrate (79.7 g, 1.56 mol). The resulting mixture was stirred at 20°C for 2 h. Combine 4 reaction batches and add H to them₂ O (10 L) and extract with DCM (3×8 L). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 5-33%) to provideTitle compound (800 g, 58%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.70-12.78 (m, 1H), 4.25-4.20 (m, 2H), 3.14-3.07 (m, 1H), 2.89-2.82 (m, 2H), 2.68-2.62 (m, 1H), 1.27 (br s, 3H), 1.20 (br s, 3H), 1.04-1.00 (m, 1H), 0.31-0.29 (m, 1H), 0.08-0.02 (m, 1H); LC/MSm/z (M+H)⁺ = 221.0.

藉由對掌性SFC (Chiral Tech OZ-H 250 mm × 4.6 mm × 5 µm管柱，移動相為CO_2(g) / MeOH=80:20 (含有0.2% NH₄ ⁺ (7N NH₃ 於MeOH中))，且流速為3.0 mL/min)分離製備物6。 6a：滯留時間= 3.89 min, 100%ee, [α]²⁰ _D = +67.1 (c = 4.2, MeOH)；LC/MSm/z (M+H)⁺ = 221.1。 6b：滯留時間= 4.76 min, 98.9%ee；[α]²⁰ _D = -80.2 (c = 4.7, MeOH)；¹ H NMR (400 MHz, DMSO-d₆ ) δ 13.44-12.80 (m, 1H), 4.20-4.12 (m, 2H), 3.25-3.10 (m, 1H), 3.09-2.99 (m, 1H), 2.96-2.86 (m, 1H), 2.82-2.71 (m, 1H), 2.63-2.52 (m, 1H), 1.25-1.18 (m, 3H), 1.14 (s, 3H), 1.02-0.92 (m, 1H), 0.34-0.20 (br s, 1H), 0.05-^- 0.05 (br s, 1H)。 Preparation 6a : (4aR,5aS)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate ； and Preparation 6b : (4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate

Through the SFC (Chiral Tech OZ-H 250 mm × 4.6 mm × 5 µm column, the mobile phase is CO_2(g) / MeOH=80:20 (contains 0.2% NH₄ ⁺ (7N NH₃ In MeOH)) with a flow rate of 3.0 mL/min) Isolate Preparation 6. 6a: Residence time = 3.89 min, 100%ee, [α]²⁰ _D = +67.1 (c = 4.2, MeOH); LC/MSm/z (M+H)⁺ = 221.1. 6b: Residence time = 4.76 min, 98.9%ee; [α]²⁰ _D = -80.2 (c = 4.7, MeOH);¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.44-12.80 (m, 1H), 4.20-4.12 (m, 2H), 3.25-3.10 (m, 1H), 3.09-2.99 (m, 1H), 2.96-2.86 (m, 1H), 2.82-2.71 (m, 1H), 2.63-2.52 (m, 1H), 1.25-1.18 (m, 3H), 1.14 (s, 3H), 1.02-0.92 (m, 1H), 0.34-0.20 (br s, 1H), 0.05-^- 0.05 (br s, 1H).

在0℃下，使用製備物6b (103 g, 467.6 mmol)於THF (1.25 L)中之溶液處理NaH (19.3 g, 483 mmol)於THF (500 mL)中之懸浮液。在30 min之後，在0℃下添加SEM-Cl (81.9 g, 491 mmol)且將混合物在0℃下攪拌3 h。使用NH₄ Cl飽和水溶液(500 mL)在0℃下處理混合物。使用EtOAc (3 × 500 mL)萃取混合物，使用鹽水(500 mL)洗滌，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 7-18%)純化粗產物以提供標題化合物 。 7a: (5.5 g, 3.3%);¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.43 (br. s, 2H), 4.54 - 4.28 (m, 2H), 3.55 - 3.50 (m, 2H), 3.27 - 3.23 (m, 1H), 3.12 - 3.08 (m, 1H), 2.99 - 2.97 (m, 1H), 2.71-2.67 (m, 1H), 1.60 - 1.41 (m, 3H), 1.21 (s, 3H), 1.08 - 1.05 (m, 1H), 0.89 - 0.85 (m, 2H), 0.41 - 0.39 (m, 1H), 0.21 - 0.19 (m, 1H), -0.03 (s, 9H)。 7b: (138 g, 84%)；¹ H NMR (400 MHz, DMSO-d₆ ) δ 5.64 (s, 2H), 4.32 - 4.25 (m, 2H), 3.49 - 3.44 (m, 2H), 3.20 - 3.16 (m, 1H), 2.95 - 2.88 (m, 2H), 2.67 - 2.62 (m, 1H), 1.32 - 1.28 (m, 3H), 1.21 (s, 3H), 1.05 - 0.95 (m, 1H), 0.76 - 0.72 (m, 2H), 0.33 - 0.29 (m, 1H), 0.04 - 0.01 (m, 1H), -0.1 (s, 9H)；LC/MSm/z (M+H)⁺ = 351.3。 Preparation 7a : (4aS,5aR)-5a- methyl -2-((2-( Trimethylsilyl ) Ethoxy ) methyl )-2,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate ； and Preparation 7b : (4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate

A solution of preparation 6b (103 g, 467.6 mmol) in THF (1.25 L) was used to treat a suspension of NaH (19.3 g, 483 mmol) in THF (500 mL) at 0°C. After 30 min, SEM-Cl (81.9 g, 491 mmol) was added at 0°C and the mixture was stirred at 0°C for 3 h. Use NH₄ The mixture was treated with saturated aqueous Cl (500 mL) at 0°C. The mixture was extracted with EtOAc (3 × 500 mL), washed with brine (500 mL), and dried (MgSO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/heptane = 7-18%) to provideTitle compound . 7a: (5.5 g, 3.3%);¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.43 (br. s, 2H), 4.54-4.28 (m, 2H), 3.55-3.50 (m, 2H), 3.27-3.23 (m, 1H), 3.12-3.08 (m, 1H), 2.99-2.97 (m, 1H), 2.71-2.67 (m, 1H), 1.60-1.41 (m, 3H), 1.21 (s, 3H), 1.08-1.05 (m, 1H), 0.89-0.85 (m, 2H), 0.41 -0.39 (m, 1H), 0.21-0.19 (m, 1H), -0.03 (s, 9H). 7b: (138 g, 84%);¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.64 (s, 2H), 4.32-4.25 (m, 2H), 3.49-3.44 (m, 2H), 3.20-3.16 (m, 1H), 2.95-2.88 (m, 2H), 2.67-2.62 (m , 1H), 1.32-1.28 (m, 3H), 1.21 (s, 3H), 1.05-0.95 (m, 1H), 0.76-0.72 (m, 2H), 0.33-0.29 (m, 1H), 0.04-0.01 (m, 1H), -0.1 (s, 9H); LC/MSm/z (M+H)⁺ = 351.3.

在0℃下，使用製備物7b (138 g, 393.7 mmol)於THF (1 L)中之溶液逐滴處理LiAlH₄ (14.94 g, 393.7 mmol)於THF (500 mL)中之懸浮液。將混合物在15℃下攪拌2 h。將混合物冷卻至0℃並藉由逐滴添加H₂ O (15 mL)、15% NaOH水溶液(15 mL)及H₂ O (30 mL)來依序處理，隨後添加MgSO₄ 及EtOAc (500 mL)。過濾所得混合物且濃縮濾液以提供標題化合物 (110 g, 91%)。¹ H NMR (400 MHz, CDCl₃ ) δ 5.35 - 5.23 (m, 2H), 4.64 - 4.55 (m, 2H), 3.53 - 3.49 (m, 2H), 3.06 - 3.02 (m, 1H), 2.86 - 2.81 (m, 2H), 2.67 - 2.63 (m, 1H), 2.07 - 1.90 (m, 1H), 1.24 (s, 3H), 1.05 - 1.03 (m, 1H), 0.91 - 0.87 (m, 2H), 0.39 - 0.35 (m, 1H), 0.25 - 0.22 (m, 1H), -0.03 (d, 9H)。 Preparation 8 : ((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base ) Methanol

Treat LiAlH dropwise with a solution of preparation 7b (138 g, 393.7 mmol) in THF (1 L) at 0°C₄ (14.94 g, 393.7 mmol) suspension in THF (500 mL). The mixture was stirred at 15°C for 2 h. Cool the mixture to 0°C and add H₂ O (15 mL), 15% NaOH aqueous solution (15 mL) and H₂ O (30 mL) to process sequentially, then add MgSO₄ And EtOAc (500 mL). The resulting mixture was filtered and the filtrate was concentrated to provideTitle compound (110 g, 91%).¹ H NMR (400 MHz, CDCl₃ ) δ 5.35-5.23 (m, 2H), 4.64-4.55 (m, 2H), 3.53-3.49 (m, 2H), 3.06-3.02 (m, 1H), 2.86-2.81 (m, 2H), 2.67-2.63 (m, 1H), 2.07-1.90 (m, 1H), 1.24 (s, 3H), 1.05-1.03 (m, 1H), 0.91-0.87 (m, 2H), 0.39-0.35 (m, 1H), 0.25 -0.22 (m, 1H), -0.03 (d, 9H).

使用活化MnO₂ (310 g, 3.57 mol)處理製備物8 (110.13 g, 0.36 mol)於DCM (1.5 L)中之溶液且將所得混合物在25℃下攪拌16 h。過濾混合物。濃縮濾液，且藉由層析(二氧化矽，EtOAc/PE = 3-10%)純化粗產物以提供標題化合物 (96 g, 88%)。SFC方法：Chiral Pak AD-3 150 mm × 4.6 mm × 3 µm, 5-40% (於EtOH中之0.05%二乙胺/CO_2(g) )，1.5 min, 2.5 mL/min，滯留時間= 1.466 min 97.4%, 94.8%ee。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 5.52 - 5.38 (m, 2H), 3.53 - 3.49 (m, 2H), 3.16 - 3.11 (m, 2H), 2.93 - 2.82 (m, 1H), 2.69 - 2.65 (m, 1H), 1.22 (s, 3H), 1.08 - 1.02 (m, 1H), 0.84 - 0.80 (m, 2H), 0.40 - 0.39 (m, 1H), 0.10 - 0.08 (m, 1H), -0.07 (s, 9H)；LC/MSm/z (M+H)⁺ = 307.3。 Preparation 9 : (4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- formaldehyde

Use activated MnO₂ (310 g, 3.57 mol) A solution of Preparation 8 (110.13 g, 0.36 mol) in DCM (1.5 L) was treated and the resulting mixture was stirred at 25°C for 16 h. Filter the mixture. The filtrate was concentrated, and the crude product was purified by chromatography (silica dioxide, EtOAc/PE = 3-10%) to provideTitle compound (96 g, 88%). SFC method: Chiral Pak AD-3 150 mm × 4.6 mm × 3 µm, 5-40% (0.05% diethylamine/CO in EtOH_2(g) ), 1.5 min, 2.5 mL/min, retention time = 1.466 min 97.4%, 94.8%ee.¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 5.52-5.38 (m, 2H), 3.53-3.49 (m, 2H), 3.16-3.11 (m, 2H), 2.93-2.82 (m, 1H), 2.69-2.65 (m , 1H), 1.22 (s, 3H), 1.08-1.02 (m, 1H), 0.84-0.80 (m, 2H), 0.40-0.39 (m, 1H), 0.10-0.08 (m, 1H), -0.07 ( s, 9H); LC/MSm/z (M+H)⁺ = 307.3.

平行實施26個批次之反應。使用TMSCF₃ (276 g, 1.95 mol)及NaI (75.8 g, 506 mmol)處理製備物2 (150 g, 972 mmol)於THF (1.20 L)中之溶液。將混合物在70℃下攪拌16 h。將26個反應混合物冷卻至室溫併合併。使用水(10 L)稀釋將混合物並使用MTBE (4 × 3 L)萃取。使用鹽水(8 L)洗滌有機相，乾燥(Na₂ SO₄ )，過濾並濃縮以獲得標題化合物 (4.30 kg, 83%產率)。 Preparation 10. 7,7 -Difluoro- 1 - methylspiro[ bicyclo [4.1.0] heptane- 3,2'-[1,3] dioxolane ]

26 batches of reactions were carried out in parallel. A solution of Preparation 2 (150 g, 972 mmol) in THF (1.20 L) was treated _{with TMSCF 3 (276 g, 1.95 mol) and NaI (75.8 g, 506 mmol).} The mixture was stirred at 70°C for 16 h. The 26 reaction mixtures were cooled to room temperature and combined. The mixture was diluted with water (10 L) and extracted with MTBE (4 x 3 L). The organic phase was washed with brine (8 L), dried (Na ₂ SO ₄ ), filtered and concentrated to obtain the title compound (4.30 kg, 83% yield).

平行實施5個批次之反應。使用3M HCl (2.6 L)在25℃下處理製備物10 (860 g, 4.21 mol)於THF (10 L)中之混合物。將混合物在25℃下攪拌16小時。合併5個反應液並使用MTBE (4 × 2.5 L)萃取，使用NaHCO₃ 飽和水溶液(5 L)及鹽水(5 L)洗滌。乾燥(Na₂ SO₄ )有機相，過濾並濃縮以提供標題化合物 11 (3.50 kg)；¹ H NMR (400 MHz, CDCl₃ ) δ: 2.56 (br d, 1H), 2.38-2.13 (m, 4H), 2.01-1.89 (m, 1H), 1.49-1.38 (m, 1H), 1.27 (br s, 3H) Preparation 11 : 7,7- Difluoro -1- Methyl bicyclic [4.1.0] Heptane -3- ketone

Perform 5 batches of reactions in parallel. A mixture of Preparation 10 (860 g, 4.21 mol) in THF (10 L) was treated with 3M HCl (2.6 L) at 25°C. The mixture was stirred at 25°C for 16 hours. Combine the 5 reaction solutions and extract with MTBE (4 × 2.5 L), using NaHCO₃ Wash with saturated aqueous solution (5 L) and brine (5 L). Dry (Na₂ SO₄ ) Organic phase, filtered and concentrated to provideTitle compound 11 (3.50 kg);¹ H NMR (400 MHz, CDCl₃ ) δ: 2.56 (br d, 1H), 2.38-2.13 (m, 4H), 2.01-1.89 (m, 1H), 1.49-1.38 (m, 1H), 1.27 (br s, 3H)

平行實施8個批次之反應。在0℃下，使用EtONa (112 g, 1.65 mol)逐份處理製備物11 (250 g, 1.56 mol)於EtOH (1.25 L)中之溶液。使用草酸二乙酯(242 g, 1.65 mol)在0℃下處理所得混合物。將反應混合物在25℃下攪拌1 h。合併8個批次。將混合物傾倒至3 M HCl溶液(8.00 L)中並使用DCM (3 × 2 L)萃取。使用鹽水(5 L)洗滌有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮以提供標題化合物 12 (3.20 kg, 98%產率) Preparation 12 : 2-(7,7- Difluoro -6- methyl -4- Pendant oxybicyclic ring [4.1.0] Heptane -3- base )-2- Ethyl pendant oxyacetate

The reactions of 8 batches were carried out in parallel. A solution of Preparation 11 (250 g, 1.56 mol) in EtOH (1.25 L) was treated with EtONa (112 g, 1.65 mol) at 0°C. The resulting mixture was treated with diethyl oxalate (242 g, 1.65 mol) at 0°C. The reaction mixture was stirred at 25°C for 1 h. Combine 8 batches. The mixture was poured into a 3 M HCl solution (8.00 L) and extracted with DCM (3×2 L). The organic extract was washed with brine (5 L) and dried (Na₂ SO₄ ), filtered and concentrated to provideTitle compound 12 (3.20 kg, 98% yield)

平行實施8個批次之反應。使用水合肼(76.9 g, 1.54 mol)在0℃下處理製備物12 (400 g, 1.54 mol)於EtOH (2 L)中之懸浮液。將反應液在室溫下攪拌16 h。合併8個反應液以供後處理。濃縮反應混合物並將殘餘物溶解於H₂ O (5.00 L)中，且使用EtOAc (5 × 2 L)萃取。乾燥(Na₂ SO₄ )合併之有機萃取物，過濾並濃縮。藉由在20℃下於6:1 EtOAc/EtOH (3 L)中重結晶來純化粗產物以提供標題化合物 13 (1.0 Kg)。¹ H NMR (400 MHz, CDCl₃ ) δ: 12.03-10.65 (br m, 1H), 4.38 (q, 2H), 3.30-3.04 (m, 3H), 2.79 (dd, 1H), 1.57 (br dd, 1H), 1.34-1.43 (m, 6H)；LC-MS (ES+)e/z [M+H] = 257.1 Preparation 13 : 5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate

The reactions of 8 batches were carried out in parallel. A suspension of Preparation 12 (400 g, 1.54 mol) in EtOH (2 L) was treated with hydrazine hydrate (76.9 g, 1.54 mol) at 0°C. The reaction solution was stirred at room temperature for 16 h. The 8 reaction solutions were combined for post-processing. The reaction mixture was concentrated and the residue was dissolved in H₂ O (5.00 L) and extracted with EtOAc (5 x 2 L). Dry (Na₂ SO₄ ) The combined organic extracts are filtered and concentrated. The crude product was purified by recrystallization in 6:1 EtOAc/EtOH (3 L) at 20°C to provideTitle compound 13 (1.0 Kg).¹ H NMR (400 MHz, CDCl₃ ) δ: 12.03-10.65 (br m, 1H), 4.38 (q, 2H), 3.30-3.04 (m, 3H), 2.79 (dd, 1H), 1.57 (br dd, 1H), 1.34-1.43 (m, 6H); LC-MS (ES+)e/z [M+H] = 257.1

藉由對掌性SFC使用Chiral Tech AD-H 250 mm × 21.2mm 5 µm管柱來分離製備物13，其中移動相為CO_2(g) /MeOH = 80:20 (含有於MeOH中之0.2% 7N NH₃ )且流速為200 mL/min。 SFC分析方法：Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm A = CO_2(g) ；B =於MeOH中之0.2% NH₃ (呈於MeOH中之7N NH₃ 形式)；梯度= 0-1 min 5% B, 1-9.5 min 5-60% B斜坡；9.5-10min 60-5% B斜坡。 Preparation 14 : Antipodal SFC separation of enantiomers

Separate Preparation 13 by using a Chiral Tech AD-H 250 mm × 21.2mm 5 µm column by a palm-type SFC, where the mobile phase is CO _2(g) /MeOH = 80:20 (containing 0.2% of MeOH) 7N NH ₃ ) and the flow rate is 200 mL/min. SFC analysis method: Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm A = CO _{2 (g)} ; B = 0.2% NH ₃ in MeOH (in the _{form of 7N NH 3} in MeOH); gradient = 0 -1 min 5% B, 1-9.5 min 5-60% B slope; 9.5-10min 60-5% B slope.

使用製備物14b (18.16 g, 70.87 mmol)於THF (100 mL)中之溶液經45 min逐滴處理NaH (4.25 g, 106 mmol)於THF (20 mL)中之冷卻至0℃之混合物。將混合物在0℃下攪拌1 h且然後使用於THF (80 mL)中之SEM-Cl (17.7 g, 106 mmol)逐滴處理。將所得混合物在室溫下攪拌48 h。將反應混合物緩慢傾倒於冰上並使用EtOAc萃取3次。合併有機萃取物，使用鹽水洗滌，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0-20%)純化粗產物以提供25.8 g (94%)標題化合物 。¹ H NMR (400 MHz, CDCl₃ ) δ 5.50 - 5.40 (m, 2H), 4.40 (q, 2H), 3.55 - 3.47 (m, 2H), 3.26 - 3.05 (m, 3H), 2.76 (br dd, 1H), 1.62 - 1.54 (m, 1H), 1.44 - 1.35 (m, 6H), 0.94 - 0.81 (m, 2H), -0.03 (s, 9H)；LC-MSm/z (M+H)⁺ = 387.4 Preparation 14a : (4aR,5aS)-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate , 100% ee (by SFC analysis method), residence time = 4.605 minPreparation 14b : (4aS,5aR)-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate , 99.85% ee (by SFC analysis method), residence time = 5.565 minPreparation 15 : (4aS,5aR)-5,5- Difluoro -5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Ethyl formate

A solution of preparation 14b (18.16 g, 70.87 mmol) in THF (100 mL) was used to treat a mixture of NaH (4.25 g, 106 mmol) in THF (20 mL) cooled to 0°C dropwise over 45 min. The mixture was stirred at 0°C for 1 h and then treated dropwise with SEM-Cl (17.7 g, 106 mmol) in THF (80 mL). The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was slowly poured on ice and extracted 3 times with EtOAc. The organic extracts were combined, washed with brine, and dried (MgSO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/heptane = 0-20%) to provide 25.8 g (94%)Title compound .¹ H NMR (400 MHz, CDCl₃ ) δ 5.50-5.40 (m, 2H), 4.40 (q, 2H), 3.55-3.47 (m, 2H), 3.26-3.05 (m, 3H), 2.76 (br dd, 1H), 1.62-1.54 (m, 1H), 1.44-1.35 (m, 6H), 0.94-0.81 (m, 2H), -0.03 (s, 9H); LC-MSm/z (M+H)⁺ = 387.4

在大約-5℃下，向製備物15 (25.84 g, 66.86 mmol)於THF (100 mL)中之溶液中以控制溫度介於0℃與10℃之間之速率逐滴添加LiAlH₄ 溶液(100 mL, 1M於THF中)。將混合物在0℃下再攪拌1 h並逐漸升溫至室溫，且再攪拌4 h。將混合物冷卻至-10℃並使用6 N NaOH (45 mL)逐滴處理30 min。添加額外EtOAc以幫助攪拌較稠混合物且將漿液升溫至室溫。添加無水MgSO₄ 並再繼續攪拌30 min。過濾混合物並使用EtOAc沖洗固體。濃縮濾液並乾燥以提供標題化合物 (21.89 g, 95%)。¹ H NMR (400 MHz, CDCl₃ ) δ 5.38 - 5.21 (m, 2H), 4.60 (s, 2H), 3.55 - 3.41 (m, 2H), 3.08 (br d, 1H), 2.98 - 2.83 (m, 2H), 2.79 - 2.65 (m, 1H), 2.24 (br s, 1H), 1.60 - 1.49 (m, 1H), 1.40 (br s, 3H), 0.94 - 0.80 (m, 2H), -0.03 (s, 9H)；LC-MSm/z (M+H)⁺ = 345.5。 Preparation 16 : ((4aS,5aR)-5,5- Difluoro -5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base ) Methanol

At about -5°C, to a solution of Preparation 15 (25.84 g, 66.86 mmol) in THF (100 mL), LiAlH was added dropwise at a rate that controlled the temperature between 0°C and 10°C₄ Solution (100 mL, 1M in THF). The mixture was stirred at 0°C for another 1 h and gradually warmed to room temperature, and stirred for another 4 h. The mixture was cooled to -10°C and treated dropwise with 6 N NaOH (45 mL) for 30 min. Additional EtOAc was added to help stir the thicker mixture and the slurry was warmed to room temperature. Add anhydrous MgSO₄ And continue to stir for another 30 minutes. The mixture was filtered and the solids were rinsed with EtOAc. Concentrate the filtrate and dry to provideTitle compound (21.89 g, 95%).¹ H NMR (400 MHz, CDCl₃ ) δ 5.38-5.21 (m, 2H), 4.60 (s, 2H), 3.55-3.41 (m, 2H), 3.08 (br d, 1H), 2.98-2.83 (m, 2H), 2.79-2.65 (m, 1H), 2.24 (br s, 1H), 1.60-1.49 (m, 1H), 1.40 (br s, 3H), 0.94-0.80 (m, 2H), -0.03 (s, 9H); LC-MSm/z (M+H)⁺ = 345.5.

將製備物16 (21.89 g, 63.55 mmol)於DCM (25 mL)中之溶液冷卻至0℃。在0℃下經大約20 min逐滴添加戴斯-馬丁過碘烷(Dess-Martin periodinane) (33.7 g, 79.4 mmol)於DCM (250 mL)中之溶液。使用在0℃下經45 min逐滴添加之2.2%水/DCM (50 mL)處理混合物。將混合物升溫至室溫並攪拌4 h。使用1 N NaOH (380 mL)處理混合物並攪拌30 min。分離雙相混合物。使用鹽水洗滌有機相，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0-50%)純化粗產物以提供標題化合物 (17.8 g, 82%)。¹ H NMR (400 MHz, CDCl₃ ) d 9.98 (s, 1H), 5.52-5.35 (m, 2H), 3.61-3.43 (m, 2H), 3.27-3.05 (m, 4H), 2.82-2.66 (m, 1H), 1.42 (m., 3H), 0.98-0.80 (m, 2H), 0.08 - -0.13 (m, 9H)；LC-MSm/z (M+H)⁺ = 343.3。 Preparation 17 : (4aS,5aR)-5,5- Difluoro -5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- formaldehyde

A solution of Preparation 16 (21.89 g, 63.55 mmol) in DCM (25 mL) was cooled to 0°C. A solution of Dess-Martin periodinane (33.7 g, 79.4 mmol) in DCM (250 mL) was added dropwise over about 20 min at 0°C. The mixture was treated with 2.2% water/DCM (50 mL) added dropwise over 45 min at 0°C. The mixture was warmed to room temperature and stirred for 4 h. The mixture was treated with 1 N NaOH (380 mL) and stirred for 30 min. Separate the biphasic mixture. The organic phase was washed with brine and dried (MgSO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/heptane=0-50%) to provideTitle compound (17.8 g, 82%).¹ H NMR (400 MHz, CDCl₃ ) d 9.98 (s, 1H), 5.52-5.35 (m, 2H), 3.61-3.43 (m, 2H), 3.27-3.05 (m, 4H), 2.82-2.66 (m, 1H), 1.42 (m., 3H), 0.98-0.80 (m, 2H), 0.08--0.13 (m, 9H); LC-MSm/z (M+H)⁺ = 343.3.

使用Et₃ N (624 g, 6.165 mol)處理L-丙胺酸苄基酯4-甲基苯磺酸鹽(500 g, 1.42 mol)於DMSO (3 L)中之溶液且將混合物冷卻至0℃。將1-溴-2-(2-溴乙氧基)乙烷(429 g, 1.849 mol)於DMSO (1 L)中之溶液緩慢添加至反應液中。將所得混合物在25℃下攪拌36 h。將水(3 L)及EtOAc (2 L)添加至混合物中。使用EtOAc (2 × 1 L)萃取水相。乾燥(Na₂ SO₄ )合併之有機萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 11%)純化粗產物以提供標題化合物 (290 g, 82%)。¹ H NMR (400 MHz, DMSO-d₆ ) δ 7.42 - 7.31 (m, 5H), 5.19 (s, 2H), 3.79 - 3.66 (m, 4H), 3.35 - 3.30 (m, 1H), 2.69 - 2.56 (m, 4H), 1.32 - 1.29 (m, 3H)。 Preparation 18 : (S)-2- N- 𠰌 Benzyl hydroxypropionate

Use Et₃ A solution of L-alanine benzyl 4-methylbenzenesulfonate (500 g, 1.42 mol) in DMSO (3 L) was treated with N (624 g, 6.165 mol) and the mixture was cooled to 0°C. A solution of 1-bromo-2-(2-bromoethoxy)ethane (429 g, 1.849 mol) in DMSO (1 L) was slowly added to the reaction solution. The resulting mixture was stirred at 25°C for 36 h. Water (3 L) and EtOAc (2 L) were added to the mixture. The aqueous phase was extracted with EtOAc (2×1 L). Dry (Na₂ SO₄ ) The combined organic extracts are filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 11%) to provideTitle compound (290 g, 82%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42-7.31 (m, 5H), 5.19 (s, 2H), 3.79-3.66 (m, 4H), 3.35-3.30 (m, 1H), 2.69-2.56 (m, 4H), 1.32-1.29 (m , 3H).

使用10% Pd(OH)₂ /C (29 g)在25℃下處理製備物18 (290 g, 1.56 mol)於MeOH (2.9 L)中之溶液。將混合物脫氣並使用N₂ (3次)吹掃且然後在H₂ 氣氛下攪拌36 h。藉由過濾去除固體並濃縮濾液。使用MTBE (200 mL ×2)洗滌所得殘餘物以提供標題化合物 (146 g, 79%)。SFC分析方法：Chiral Tech IC 250 mm × 4.6 mm × 5 µm, 5 - 60% MeOH (含有0.2% NH₄ ⁺ (7 N於MeOH中))/CO₂ (g), 3.0 mL/min，滯留時間= 5.88 min, 100%ee；¹ H NMR (400 MHz, DMSO-d₆ ) δ 3.56 (s, 4H), 3.18 - 3.16 (m, 1H), 2.54 - 2.53 (m, 4H), 1.17 - 1.15 (m, 3H)；LC/MSm/z (M+H)⁺ = 160.1。 Preparation 19 : (S)-2- N - 𠰌 Alkylpropionic acid

Use 10% Pd(OH)₂ /C (29 g) A solution of Preparation 18 (290 g, 1.56 mol) in MeOH (2.9 L) was treated at 25°C. Degas the mixture and use N₂ (3 times) purge and then in H₂ Stir under the atmosphere for 36 h. The solids were removed by filtration and the filtrate was concentrated. Wash the resulting residue with MTBE (200 mL × 2) to provideTitle compound (146 g, 79%). SFC analysis method: Chiral Tech IC 250 mm × 4.6 mm × 5 µm, 5-60% MeOH (containing 0.2% NH₄ ⁺ (7 N in MeOH))/CO₂ (g), 3.0 mL/min, retention time = 5.88 min, 100%ee;¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.56 (s, 4H), 3.18-3.16 (m, 1H), 2.54-2.53 (m, 4H), 1.17-1.15 (m, 3H); LC/MSm/z (M+H)⁺ = 160.1.

使用草醯氯(30.5 g, 240 mmol)在0℃下處理2-(四氫-2H -吡喃-4-基)乙酸(17.3 g, 120 mmol)於DCM (400 mL)及DMF (1 mL)中之溶液。然後將混合物升溫至20℃並攪拌16 h。濃縮混合物以得到標題化合物 (19.5 g，定量)。 Preparation 20 : 2-( Tetrahydro -2 H- Pyran -4- base ) Acetyl Chloride

Treat 2-(tetrahydro-2H -A solution of pyran-4-yl)acetic acid (17.3 g, 120 mmol) in DCM (400 mL) and DMF (1 mL). The mixture was then warmed to 20°C and stirred for 16 h. Concentrate the mixture to getTitle compound (19.5 g, quantitative).

使用n -BuLi (47.9 mL, 120 mmol)在-78℃下處理20 (14.2 g, 79.9 mmol)於THF (500 mL)中之溶液。然後將混合物在-78℃下攪拌2 h。在-78℃下添加2-(四氫-2H -吡喃-4-基)乙醯氯(19.5 g, 120 mmol)於THF (100 mL)中之溶液並再攪拌2 h。然後將混合物升溫至20℃且然後攪拌16 h。使用NH₄ Cl飽和水溶液(400 mL)處理反應液並分離所得雙相混合物。乾燥(Na₂ SO₄ )有機相並濃縮。將殘餘物懸浮於DCM/PE (50 mL/300 mL)中並在-50℃下攪拌30 min。收集固體並乾燥以得到標題化合物 (21.5 g, 89%產率)。LC/MSm/z (M+H) = 303.8。 Preparation twenty one : (R)-4- Benzyl -3-(2-( Tetrahydro -2 H- Pyran -4- base ) Acetyl ) Oxazolidine -2- ketone

usen -BuLi (47.9 mL, 120 mmol) treat a solution of 20 (14.2 g, 79.9 mmol) in THF (500 mL) at -78°C. The mixture was then stirred at -78°C for 2 h. Add 2-(tetrahydro-2H -Pyran-4-yl)acetoxychloride (19.5 g, 120 mmol) in THF (100 mL) and stirred for another 2 h. The mixture was then warmed to 20°C and then stirred for 16 h. Use NH₄ The reaction solution was treated with saturated aqueous Cl (400 mL) and the resulting biphasic mixture was separated. Dry (Na₂ SO₄ ) Organic phase and concentrated. The residue was suspended in DCM/PE (50 mL/300 mL) and stirred at -50°C for 30 min. Collect the solid and dry to getTitle compound (21.5 g, 89% yield). LC/MSm/z (M+H) = 303.8.

使用NaHMDS (1M於THF中，106 mL)在-78℃下處理製備物21 (21.5 g, 70.8 mmol)於THF (200 mL)中之溶液。在-78℃下，將混合物攪拌1 h並使用碘甲烷(50.3 g, 354 mmol)處理。將反應混合物在-78℃下攪拌2 h且然後經16 h逐漸升溫至20℃。使用NH₄ Cl飽和水溶液(300 mL)處理反應混合物並分離雙相混合物。使用鹽水洗滌有機層，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE: 0-100%)純化粗產物以得到標題化合物 (15.5 g, 69%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.32 - 7.11 (m, 5H), 4.62 (ddt, 1H), 4.20 - 4.07 (m, 2H), 4.02 (dd, 1H), 3.94 (dd, 1H), 3.65 - 3.54 (m, 1H), 3.33 (tt, 2H), 3.22 (dd, 1H), 2.72 (dd, 1H), 1.97 - 1.87 (m, 1H), 1.64 - 1.56 (m, 1H), 1.58 - 1.51 (m, 1H), 1.41 - 1.26 (m, 2H), 1.15 (d, 3H)；LC/MSm/z (M+H)⁺ = 318.3。 Preparation 21a : (R)-4- Benzyl -3-((R)2-( Tetrahydro -2 H- Pyran -4- base ) Acrylic ) Oxazolidine -2- ketone

A solution of Preparation 21 (21.5 g, 70.8 mmol) in THF (200 mL) was treated with NaHMDS (1M in THF, 106 mL) at -78°C. At -78°C, the mixture was stirred for 1 h and treated with methyl iodide (50.3 g, 354 mmol). The reaction mixture was stirred at -78°C for 2 h and then gradually warmed to 20°C over 16 h. Use NH₄ The reaction mixture was treated with saturated aqueous Cl (300 mL) and the biphasic mixture was separated. The organic layer was washed with brine and dried (MgSO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE: 0-100%) to obtainTitle compound (15.5 g, 69%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.32-7.11 (m, 5H), 4.62 (ddt, 1H), 4.20-4.07 (m, 2H), 4.02 (dd, 1H), 3.94 (dd, 1H), 3.65-3.54 (m, 1H), 3.33 (tt, 2H), 3.22 (dd, 1H), 2.72 (dd, 1H), 1.97-1.87 (m, 1H), 1.64-1.56 (m, 1H), 1.58-1.51 (m, 1H), 1.41- 1.26 (m, 2H), 1.15 (d, 3H); LC/MSm/z (M+H)⁺ = 318.3.

使用LiOH·H₂ O (10.2 g, 244 mmol)及30% H₂ O₂ 水溶液(27.7 g, 244 mmol)在0℃下處理製備物21a (15.5 g, 48.8 mmol)於THF/H₂ O (410 mL/255 mL)中之溶液。將混合物在0℃下攪拌1.5 h且在20℃下然後攪拌1.5 h。使用Na₂ SO₃ 飽和水溶液(300 mL)處理混合物且在真空中去除有機溶劑。使用DCM (2 × 200 mL)洗滌混合物且然後使用濃HCL處理直至達到pH = 1為止。使用DCM (3 × 200 mL)萃取混合物，且合併萃取物並乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 22 (6.12 g, 79%產率)。(參考文獻：Evans, D. A等人，J. Am. Chem. Soc. 1984,106 , 1154−1156)¹ H NMR (400 MHz, CDCl₃ ) δ 4.07 - 3.93 (m, 2H), 3.39 (dt, 2H), 2.30 (p, 1H), 1.87 - 1.77 (m, 1H), 1.68 - 1.56 (m, 2H), 1.51 - 1.28 (m, 2H), 1.17 (d, 3H)。[a]²⁰ _D = - 17.98 (c = 0.3 g/100 mL, EtOH)；對掌性SFC (MeOH/CO₂ , Chiral Tech IG，在10 min內5 - 60%，250 mm × 4.6 mm × 5 µm)；滯留時間= 3.42 min, 97% ee。 Preparation 22 : (R)-2-( tetrahydro - 2H - pyran- 4 -yl ) propionic acid

Use LiOH·H ₂ O (10.2 g, 244 mmol) and 30% H ₂ O ₂ aqueous solution (27.7 g, 244 mmol) at 0℃ to treat preparation 21a (15.5 g, 48.8 mmol) in THF/H ₂ O ( 410 mL/255 mL) in the solution. The mixture was stirred at 0°C for 1.5 h and then at 20°C for 1.5 h. The _{mixture was treated with saturated aqueous Na 2} SO ₃ (300 mL) and the organic solvent was removed in vacuo. The mixture was washed with DCM (2×200 mL) and then treated with concentrated HCL until pH=1 was reached. The mixture was extracted with DCM (3×200 mL), and the extracts were combined and dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound 22 (6.12 g, 79% yield). (Reference: Evans, D. A, et al., J. Am. Chem. Soc. 1984, 106 , 1154−1156) ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.07-3.93 (m, 2H), 3.39 ( dt, 2H), 2.30 (p, 1H), 1.87-1.77 (m, 1H), 1.68-1.56 (m, 2H), 1.51-1.28 (m, 2H), 1.17 (d, 3H). [a] ²⁰ _D =-17.98 (c = 0.3 g/100 mL, EtOH); opposing SFC (MeOH/CO ₂ , Chiral Tech IG, 5-60% in 10 minutes, 250 mm × 4.6 mm × 5 µm); residence time = 3.42 min, 97% ee.

以類似於製備物22 (R)-2-(四氫-2H -吡喃-4-基)丙酸之方式在步驟2中使用(S)-4-苄基噁唑啶-2-酮來製備該酸。¹ H NMR (400 MHz, CDCl₃ ) δ 4.07 - 3.93 (m, 2H), 3.39 (tt, 2H), 2.30 (p, 1H), 1.81 (tdt, 1H), 1.61 (dddq, 2H), 1.51 - 1.28 (m, 2H), 1.17 (d, 3H)。[a]²⁰ _D =+19.99 (c =0.3 g/100 mL, EtOH) Preparation 23 : (S)-2-( tetrahydro - 2H - pyran- 4 -yl ) propionic acid

Use (S)-4-benzyloxazolidin-2-one in step 2 in a manner similar to Preparation 22 (R)-2-(tetrahydro- 2H-pyran-4-yl)propionic acid To prepare the acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.07-3.93 (m, 2H), 3.39 (tt, 2H), 2.30 (p, 1H), 1.81 (tdt, 1H), 1.61 (dddq, 2H), 1.51- 1.28 (m, 2H), 1.17 (d, 3H). [a] ²⁰ _D =+19.99 (c =0.3 g/100 mL, EtOH)

在0℃下，向2-溴丙酸(5.0 g, 32.7 mmol)於DCM (100 mL)中之溶液中逐滴添加Et₃ N (3.64 g, 36.0 mmol)，隨後添加氯甲酸苄基酯(5.58 g, 32.7 mmol)。在10 min之後，添加DMAP (399 mg, 3.27 mmol)並將混合物在30℃下攪拌4 h。將混合物傾倒至1M HCl (15 mL)及鹽水(80 mL)中。使用DCM (2 × 80 mL)萃取混合物。合併有機萃取物，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE, 0-5%)純化粗產物以提供標題化合物 (4.81 g, 86%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.38 - 7.27 (m, 5H), 5.22 - 5.10 (m, 2H), 4.43 - 4.37 (m, 1H), 1.80 (d, 3H)；LC/MSm/z (M+Na)⁺ = 267.0。 Preparation twenty four : 2- Benzyl bromopropionate

At 0°C, add Et dropwise to a solution of 2-bromopropionic acid (5.0 g, 32.7 mmol) in DCM (100 mL)₃ N (3.64 g, 36.0 mmol) followed by benzyl chloroformate (5.58 g, 32.7 mmol). After 10 min, DMAP (399 mg, 3.27 mmol) was added and the mixture was stirred at 30°C for 4 h. The mixture was poured into 1M HCl (15 mL) and brine (80 mL). The mixture was extracted with DCM (2×80 mL). Combine the organic extracts and dry (MgSO₄ ), filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE, 0-5%) to provideTitle compound (4.81 g, 86%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.38-7.27 (m, 5H), 5.22-5.10 (m, 2H), 4.43-4.37 (m, 1H), 1.80 (d, 3H); LC/MSm/z (M+Na)⁺ = 267.0.

使用NaH (475 mg, 11.9 mmol)在5℃下處理嗎啉-3-酮(750 mg, 7.42 mmol)於THF (49 mL)中之溶液。在攪拌30 min之後，逐滴添加製備物24 (16 g, 8.90 mmol)。在25℃下攪拌3 h之後，使用NH₄ Cl飽和水溶液(30 mL)及水(20 mL)稀釋混合物。使用EtOAc (2 × 60 mL)萃取混合物且乾燥(MgSO₄ )合併之萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0- 70%)純化粗產物以得到標題化合物 25 (256 mg, 13%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.41 - 7.30 (m, 5H), 5.33 (q, 1H), 5.22 - 5.09 (m, 2H), 4.22 (s, 2H), 3.96 - 3.77 (m, 2H), 3.52 - 3.20 (m, 2H), 1.45 (d, 3H)。 Preparation 25 : 2-(3- Pendant Oxygen - N - 𠰌 Linyl ) Benzyl propionate

A solution of morpholin-3-one (750 mg, 7.42 mmol) in THF (49 mL) was treated with NaH (475 mg, 11.9 mmol) at 5°C. After stirring for 30 min, preparation 24 (16 g, 8.90 mmol) was added dropwise. After stirring for 3 h at 25°C, use NH₄ The mixture was diluted with saturated aqueous Cl (30 mL) and water (20 mL). Use EtOAc (2 × 60 mL) to extract the mixture and dry (MgSO₄ ) The combined extracts are filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE=0-70%) to obtainTitle compound 25 (256 mg, 13%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.41-7.30 (m, 5H), 5.33 (q, 1H), 5.22-5.09 (m, 2H), 4.22 (s, 2H), 3.96-3.77 (m, 2H), 3.52-3.20 (m, 2H) ), 1.45 (d, 3H).

向製備物25 (256 mg, 0.98 mmol)於MeOH (10 mL)中之混合物中添加10% Pd/C (50%於水中，207 mg, 0.19 mmol)。將混合物在H₂ (1 atm)及25℃下攪拌16 h。過濾反應液並使用MeOH (3 × 20 mL)洗滌固體。濃縮濾液以得到標題化合物 26 (167 mg, 99%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.15 (bs, 1H), 5.16 (d, 1H), 4.24 (d, 2H), 4.06 - 3.82 (m, 2H), 3.55 - 3.28 (m, 2H), 1.45 (dd, 3H)。 Preparation 26 : 2-(3- Pendant Oxygen - N - 𠰌 Linyl ) Propionic acid

To a mixture of Preparation 25 (256 mg, 0.98 mmol) in MeOH (10 mL) was added 10% Pd/C (50% in water, 207 mg, 0.19 mmol). Put the mixture in H₂ (1 atm) and stirring at 25°C for 16 h. The reaction solution was filtered and the solid was washed with MeOH (3×20 mL). Concentrate the filtrate to obtainTitle compound 26 (167 mg, 99%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.15 (bs, 1H), 5.16 (d, 1H), 4.24 (d, 2H), 4.06-3.82 (m, 2H), 3.55-3.28 (m, 2H), 1.45 (dd, 3H).

在20℃下，向5-氯-2-甲基-4-硝基苯胺(4.0 g, 21.4 mmol)及製備物19 (4.09 g 25.7 mmol)於吡啶(70 mL)中之溶液中添加EDCI (8.84 g, 46.1 mmol)。將混合物在20℃下攪拌16 h。使用NH₄ Cl飽和水溶液(100 mL)處理混合物並使用EtOAc (3 × 100 mL)萃取。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。使用MTBE (100 mL)研磨粗產物以提供標題化合物 (4.8 g, 68%)。¹ H NMR (400 MHz, CDCl₃ ) δ 9.83 (s, 1H), 8.68 (s, 1H), 7.87 (s, 1H), 3.87 - 378 (m, 4H), 3.35 - 3.29 (m, 1H), 2.72 – 2.62 (m, 2H), 2.37 (s, 3H), 1.39 - 1.38 (m, 3H)。 Preparation 27: (S) - N - (5- chloro-2-methyl-4-nitrophenyl) -2- N - propan-quinolyl 𠰌 Amides

At 20°C, to a solution of 5-chloro-2-methyl-4-nitroaniline (4.0 g, 21.4 mmol) and Preparation 19 (4.09 g 25.7 mmol) in pyridine (70 mL) was added EDCI ( 8.84 g, 46.1 mmol). The mixture was stirred at 20°C for 16 h. The _{mixture was treated with saturated aqueous NH 4} Cl (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was triturated using MTBE (100 mL) to provide the title compound (4.8 g, 68%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.83 (s, 1H), 8.68 (s, 1H), 7.87 (s, 1H), 3.87-378 (m, 4H), 3.35-3.29 (m, 1H), 2.72 – 2.62 (m, 2H), 2.37 (s, 3H), 1.39-1.38 (m, 3H).

在0℃下，向製備物27 (5.50 g, 16.8 mmol)於THF (75 mL)中之溶液中添加KOtBu (2.07 g, 18.5 mmol)。將混合物在0℃下攪拌1 h且在0℃下逐滴添加碘甲烷(2.62 g, 18.5 mmol)於THF (15 mL)中之溶液。將混合物在25℃下攪拌16 h。使用NH₄ Cl飽和水溶液(100 mL)處理反應液並使用EtOAc (2 × 100 mL)萃取。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮以提供標題化合物 (5.1 g, 89%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.92 - 7.81 (m, 1H), 7.72 (s, 0.5H), 7.32 (s, 0.5H), 3.79 - 3.47 (m, 4H), 3.21 - 3.19 (m, 3H), 3.39 - 2.83 (m, 1H), 2.62 - 2.51 (m, 2H), 2.43 - 2.29 (m, 3H), 2.22 - 2.16 (m, 2H), 1.18 - 1.11 (m, 3H)。 Preparation 28: (S) -N- (5- chloro-2-methyl-4-nitrophenyl) - N - methyl -2- N - propan-quinolyl 𠰌 Amides

At 0°C, to a solution of Preparation 27 (5.50 g, 16.8 mmol) in THF (75 mL) was added KOtBu (2.07 g, 18.5 mmol). The mixture was stirred at 0°C for 1 h and a solution of methyl iodide (2.62 g, 18.5 mmol) in THF (15 mL) was added dropwise at 0°C. The mixture was stirred at 25°C for 16 h. The _{reaction solution was treated with saturated aqueous NH 4} Cl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to provide the title compound (5.1 g, 89%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92-7.81 (m, 1H), 7.72 (s, 0.5H), 7.32 (s, 0.5H), 3.79-3.47 (m, 4H), 3.21-3.19 (m , 3H), 3.39-2.83 (m, 1H), 2.62-2.51 (m, 2H), 2.43-2.29 (m, 3H), 2.22-2.16 (m, 2H), 1.18-1.11 (m, 3H).

向製備物28 (320 g 936.3 mmol)於4-甲氧基苄基胺(513.7 g, 3.74 mol)中之混合物中添加乙酸銨(72.2 g, 936.3 mmol)。將混合物在100℃下加熱16 h。使用EtOAc (1.5 L)稀釋混合物並使用NH₄ Cl飽和水溶液(3 × 1.5 L)洗滌，且濃縮。藉由層析(二氧化矽，MeOH/DCM = 0-10%)純化粗產物以提供固體形式之標題化合物 (261 g, 64%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.38 - 8.02 (m, 1H), 7.26 - 7.22 (m, 2H), 6.94 - 6.98 (m, 2H), 6.79 - 6.48 (m, 1H), 4.57 - 4.47 (m, 2H), 3.87 - 3.81 (m, 3H), 3.61 - 3.51 (m, 5H), 3.14 - 3.11 (m, 3H), 3.03 - 2.83 (m, 1H), 2.56 - 2.40 (m, 2H), 2.30 - 2.04 (m, 4H), 1.14 - 1.01 (m, 3H)。 Preparation 29 : (S) -N -(5-((4 -methoxybenzyl ) amino )-2- methyl- 4 -nitrophenyl ) -N -methyl -2- N- 𠰌 Hydroxypropanamide

To a mixture of Preparation 28 (320 g 936.3 mmol) in 4-methoxybenzylamine (513.7 g, 3.74 mol) was added ammonium acetate (72.2 g, 936.3 mmol). The mixture was heated at 100°C for 16 h. The mixture was diluted with EtOAc (1.5 L) and _{washed with saturated aqueous NH 4} Cl (3×1.5 L), and concentrated. The crude product was purified by chromatography (silica dioxide, MeOH/DCM=0-10%) to provide the title compound (261 g, 64%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38-8.02 (m, 1H), 7.26-7.22 (m, 2H), 6.94-6.98 (m, 2H), 6.79-6.48 (m, 1H), 4.57-4.47 (m, 2H), 3.87-3.81 (m, 3H), 3.61-3.51 (m, 5H), 3.14-3.11 (m, 3H), 3.03-2.83 (m, 1H), 2.56-2.40 (m, 2H) , 2.30-2.04 (m, 4H), 1.14-1.01 (m, 3H).

向製備物29 (256 g, 578.5 mmol)於DCM (1.25 L)中之溶液中添加TFA (1.28 L, 17.3 mol)且將混合物在25℃下攪拌2 h。濃縮混合物且然後在DCM (1 L)中稀釋。使用飽和Na₂ CO₃ 將所得混合物調節至約pH 9且然後使用DCM (2 × 1 L)萃取。使用鹽水(1 L)洗滌合併之有機層，藉由Na₂ SO₄ 乾燥，過濾並濃縮濾液。將殘餘物溶於DCM (500 mL)中，向其中逐滴添加4 M HCl/二噁烷(1 L)並攪拌0.5 h。濃縮混合物且添加DCM (800 mL)。將所得混合物攪拌16 h。過濾混合物，且在真空中乾燥所得濾餅以提供固體形式之(S)-N -(4-胺基-2-甲基-5-硝基苯基)-N -甲基-2-N -𠰌啉基丙醯胺HCl鹽(200 g)。以三個單獨批次，向氫化器皿中裝填上述(S)-N-(4-胺基-2-甲基-5-硝基苯基)-N -甲基-2-N -𠰌啉基丙醯胺(66.6 g, 206.6 mmol)及MeOH (900 mL)。向反應器皿中添加10% Pd/C (13 g, 41.32 mmol)且使用N₂ 吹掃混合物，隨後使用H₂ 吹掃。在50 psi H₂ 及40℃下對反應液實施氫化48 h。過濾(2×)反應混合物且使用MeOH (3 × 500 mL)洗滌濾液。濃縮濾液以得到殘餘物。將殘餘物溶於MeOH (1 L)中，向其中添加Na₂ CO₃ (41.9 g, 395 mmol)且將混合物在25℃下攪拌1 h。過濾混合物，使用MeOH (5 × 200 mL)洗滌。濃縮濾液。藉由層析(二氧化矽，0-10% DCM:MeOH梯度)純化殘餘物以提供標題化合物 (159.4 g, 89%產率)。SFC方法：Chiralpak IB N-5 250 mm × 4.6 mm × 5 µm，在1 min內5% (於異丙醇中之0.2%異丙胺/CO_2(g) )，然後在8 min內升至60%，2.5 mL/min，滯留時間= 8.636 min, 98.42%, 96.85%ee。¹ H NMR (400 MHz, CDCl₃ ) δ 6.60 (s, 0.5H), 6.59 (s, 0.5H), 6.56 (s, 0.5H), 6.42 (s, 0.5H), 6.56 - 6.42 (m, 1H), 3.71 - 3.60 (m, 4H), 3.40 (br s, 4H), 3.17 - 3.07 (m, 4H), 2.66 - 2.57 (m, 2H), 2.40 - 2.31 (m, 2H), 2.16 (s, 1.5H), 2.06 (s, 1.5H), 1.19 - 1.12 (m, 3H)；LC/MSm/z (M+H)⁺ = 293.2 Preparation 30 : (S)- N -(4,5- Diamine group -2- Methyl phenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

To a solution of Preparation 29 (256 g, 578.5 mmol) in DCM (1.25 L) was added TFA (1.28 L, 17.3 mol) and the mixture was stirred at 25°C for 2 h. The mixture was concentrated and then diluted in DCM (1 L). Use saturated Na₂ CO₃ The resulting mixture was adjusted to about pH 9 and then extracted with DCM (2×1 L). Use brine (1 L) to wash the combined organic layer, with Na₂ SO₄ Dry, filter and concentrate the filtrate. The residue was dissolved in DCM (500 mL), 4 M HCl/dioxane (1 L) was added dropwise thereto and stirred for 0.5 h. The mixture was concentrated and DCM (800 mL) was added. The resulting mixture was stirred for 16 h. The mixture is filtered, and the resulting filter cake is dried in vacuum to provide (S)- in solid formN -(4-Amino-2-methyl-5-nitrophenyl)-N -Methyl-2-N -Linylpropanamide HCl salt (200 g). In three separate batches, fill the hydrogenation vessel with the above (S)-N-(4-amino-2-methyl-5-nitrophenyl)-N -Methyl-2-N -Linylpropanamide (66.6 g, 206.6 mmol) and MeOH (900 mL). Add 10% Pd/C (13 g, 41.32 mmol) to the reaction vessel and use N₂ Purge the mixture, then use H₂ Purge. At 50 psi H₂ And hydrogenation was performed on the reaction solution at 40°C for 48 h. The reaction mixture was filtered (2×) and the filtrate was washed with MeOH (3×500 mL). The filtrate was concentrated to obtain a residue. Dissolve the residue in MeOH (1 L) and add Na to it₂ CO₃ (41.9 g, 395 mmol) and the mixture was stirred at 25°C for 1 h. The mixture was filtered and washed with MeOH (5×200 mL). The filtrate was concentrated. The residue was purified by chromatography (silica dioxide, 0-10% DCM:MeOH gradient) to provideTitle compound (159.4 g, 89% yield). SFC method: Chiralpak IB N-5 250 mm × 4.6 mm × 5 µm, 5% (0.2% isopropylamine/CO in isopropanol) within 1 min_2(g) ), and then rise to 60% within 8 min, 2.5 mL/min, retention time = 8.636 min, 98.42%, 96.85%ee.¹ H NMR (400 MHz, CDCl₃ ) δ 6.60 (s, 0.5H), 6.59 (s, 0.5H), 6.56 (s, 0.5H), 6.42 (s, 0.5H), 6.56-6.42 (m, 1H), 3.71-3.60 (m, 4H ), 3.40 (br s, 4H), 3.17-3.07 (m, 4H), 2.66-2.57 (m, 2H), 2.40-2.31 (m, 2H), 2.16 (s, 1.5H), 2.06 (s, 1.5 H), 1.19-1.12 (m, 3H); LC/MSm/z (M+H)⁺ = 293.2

以類似於製備物30之方式自(±)-2-N -𠰌啉基丙酸開始來製備標題化合物 31；LC/MSm/z (M+H)⁺ = 293.3。 Preparation 31 : N -(4,5- Diamine group -2- Methyl phenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

From (±)-2- in a manner similar to Preparation 30N -𠰌Linylpropionic acid starts to prepareTitle compound 31; LC/MSm/z (M+H)⁺ = 293.3.

類似於製備物30自3-氯-4-硝基苯胺及製備物19開始來製備標題化合物 。¹ H NMR (400 MHz, CDCl₃ ) δ = 6.68 (d, 1H), 6.60 - 6.47 (m, 2H), 3.75 - 3.61 (m, 4H), 3.54 - 3.37 (m, 2H), 3.26 (q, 1H), 3.21 (s, 3H), 2.64 - 2.55 (m, 2H), 2.47 - 2.35 (m, 2H), 1.15 (d, 3H) Preparation 32 : (S)- N -(3,4- Diaminophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Similar to preparation 30, it was prepared starting from 3-chloro-4-nitroaniline and preparation 19Title compound .¹ H NMR (400 MHz, CDCl₃ ) δ = 6.68 (d, 1H), 6.60-6.47 (m, 2H), 3.75-3.61 (m, 4H), 3.54-3.37 (m, 2H), 3.26 (q, 1H), 3.21 (s, 3H) , 2.64-2.55 (m, 2H), 2.47-2.35 (m, 2H), 1.15 (d, 3H)

在攪拌及25℃下，將5-氯-2-乙基苯胺(405 mg, 2.6 mmol)添加至Ac₂ O (10 mL, 110 mmol)中。將反應混合物攪拌3 h並過濾以收集沈澱物。使用水(3 × 15 mL)沖洗固體並乾燥以得到標題化合物 (496 mg, 96%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.91 (s, 1H), 7.12 (t, 2H), 6.96 (s, 1H), 2.56 (q, 2H), 2.21 (s, 3H), 1.22 (t, 3H)；LC/MSm/z (M+H) =197.9； Preparation 33 : N -(5- chlorine -2- Ethyl phenyl ) Acetamide

Under stirring and at 25°C, 5-chloro-2-ethylaniline (405 mg, 2.6 mmol) was added to Ac₂ O (10 mL, 110 mmol). The reaction mixture was stirred for 3 h and filtered to collect the precipitate. Rinse the solid with water (3 × 15 mL) and dry to obtainTitle compound (496 mg, 96%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.91 (s, 1H), 7.12 (t, 2H), 6.96 (s, 1H), 2.56 (q, 2H), 2.21 (s, 3H), 1.22 (t, 3H); LC/MSm/z (M+H) =197.9;

在0℃下冷卻製備物33 (496mg 2.51 mmol)於濃H₂ SO₄ (2 mL)中之溶液並使用KNO₃ (254 mg, 2.51 mmol)逐份處理，且同時保持內部溫度低於5℃。將所得混合物在介於0-5℃之間之溫度下攪拌4 h。將混合物傾倒至水(30 mL)中並攪拌10 min。過濾混合物並使用水(3 × 20 mL)洗滌所收集固體，且在真空下乾燥以得到標題化合物 (600 mg, 99%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.47 (s, 1H), 7.85 (d, 1H), 7.18 (s, 1H), 2.70 - 2.59 (m, 2H), 2.29 (s, 3H), 1.34 (t, 3H)；LC/MSm/z (M+H) = 242.9 Preparation 34 : N -(5- chlorine -2- Ethyl -4- Nitrophenyl ) Acetamide

Cool Preparation 33 (496mg 2.51 mmol) at 0°C in concentrated H₂ SO₄ (2 mL) and use KNO₃ (254 mg, 2.51 mmol) in portions while keeping the internal temperature below 5°C. The resulting mixture was stirred at a temperature between 0-5°C for 4 h. The mixture was poured into water (30 mL) and stirred for 10 min. The mixture was filtered and the collected solids were washed with water (3 × 20 mL) and dried under vacuum to obtainTitle compound (600 mg, 99%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.47 (s, 1H), 7.85 (d, 1H), 7.18 (s, 1H), 2.70-2.59 (m, 2H), 2.29 (s, 3H), 1.34 (t, 3H); LC/MSm/z (M+H) = 242.9

使用NaOH (371 mg, 9.27 mmol)在25℃下處理製備物34 (450 mg, 1.85 mmol)於EtOH (10 mL)及水(5 mL)中之溶液。將所得混合物在80℃下加熱16 h。將額外NaOH (74.2 mg, 1.85 mmol)添加至混合物中並在80℃下再繼續加熱16 h。濃縮混合物，使用水(20 mL)稀釋並使用EtOAc (2 × 20 mL)萃取。濃縮合併之有機層並藉由層析(二氧化矽，EtOAc/PE = 0 - 15%)純化以得到標題化合物 (278 mg, 74%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.88 (s, 1H), 6.70 (s, 1H), 4.29 (s, 2H), 2.54 - 2.43 (m, 2H), 1.29 (t, 3H)；LC/MSm/z (M+H) = 200.9。 Preparation 35 : 5- chlorine -2- Ethyl -4- Nitroaniline

A solution of preparation 34 (450 mg, 1.85 mmol) in EtOH (10 mL) and water (5 mL) was treated with NaOH (371 mg, 9.27 mmol) at 25°C. The resulting mixture was heated at 80°C for 16 h. Additional NaOH (74.2 mg, 1.85 mmol) was added to the mixture and heating was continued at 80°C for another 16 h. The mixture was concentrated, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was concentrated and purified by chromatography (silica dioxide, EtOAc/PE = 0-15%) to obtainTitle compound (278 mg, 74%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.88 (s, 1H), 6.70 (s, 1H), 4.29 (s, 2H), 2.54-2.43 (m, 2H), 1.29 (t, 3H); LC/MSm/z (M+H) = 200.9.

使用製備物19 (1.22 g, 7.69 mmol)及EDCI (1.46 g, 12.8 mmol)在20℃下處理3-氟-4-硝基苯胺(1.0 g, 6.41 mmol)於吡啶(20 mL)中之溶液。將混合物攪拌15 h，濃縮並使用EtOAc/H₂ O (150 mL/50 mL)稀釋。分離有機層並使用EtOAc (50 mL)萃取水層。合併有機萃取物，使用鹽水洗滌，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗產物以提供標題化合物 (1.36 g, 72%)。LC/MSm/z (M+H)⁺ = 298.0。 Preparation 36. (S)- N -(3- fluorine -4- Nitrophenyl )-2- N - 𠰌 Hydroxypropionamide

Use Preparation 19 (1.22 g, 7.69 mmol) and EDCI (1.46 g, 12.8 mmol) to treat a solution of 3-fluoro-4-nitroaniline (1.0 g, 6.41 mmol) in pyridine (20 mL) at 20°C . The mixture was stirred for 15 h, concentrated and used EtOAc/H₂ Dilute with O (150 mL/50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). The organic extracts were combined, washed with brine, and dried (MgSO₄ ), filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 0-100%) to provideTitle compound (1.36 g, 72%). LC/MSm/z (M+H)⁺ = 298.0.

使用NaH (274 mg, 6.86 mmol)在0℃下處理製備物36 (1.36 g, 4.58 mmol)於THF (60 mL)中之溶液。在30 min之後，添加碘甲烷(0.43 mL, 6.86 mmol)並將混合物攪拌16 h。使用NH₄ Cl飽和水溶液(1 mL)處理混合物且然後分配於EtOAc與H₂ O (150 mL/50 mL)之間。分離有機層並使用EtOAc (100 mL)萃取水層。收集有機萃取物，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗產物以提供標題化合物 (410 mg, 29%)。LC/MSm/z (M+H)⁺ = 312.1。 Preparation 37. (S)- N -(3- fluorine -4- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 36 (1.36 g, 4.58 mmol) in THF (60 mL) was treated with NaH (274 mg, 6.86 mmol) at 0°C. After 30 min, methyl iodide (0.43 mL, 6.86 mmol) was added and the mixture was stirred for 16 h. Use NH₄ The mixture was treated with saturated aqueous Cl (1 mL) and then partitioned between EtOAc and H₂ O (150 mL/50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). Collect organic extracts and dry (MgSO₄ ), filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 0-100%) to provideTitle compound (410 mg, 29%). LC/MSm/z (M+H)⁺ = 312.1.

使用濃NH₄ OH (10 mL)在20℃下處理製備物37 (370 mg, 1.19 mmol)於EtOH (30 mL)中之溶液。將混合物在70℃下攪拌15 h且使用EtOAc/H₂ O (150/50 mL)稀釋混合物。分離有機層並使用EtOAc (50 mL)萃取水層。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾，並濃縮以得到標題化合物 (366 mg, 99%)。LC/MSm/z (M+H)⁺ = 309.1 Preparation 38. (S)- N -(3- Amino -4- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use concentrated NH₄ A solution of preparation 37 (370 mg, 1.19 mmol) in EtOH (30 mL) was treated with OH (10 mL) at 20°C. The mixture was stirred at 70°C for 15 h and EtOAc/H was used₂ The mixture was diluted with O (150/50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filter, and concentrate to getTitle compound (366 mg, 99%). LC/MSm/z (M+H)⁺ = 309.1

使用Br₂ (140 mg, 0.88 mmol)在20℃下處理製備物38 (270 mg,0.88 mmol)於AcOH (10 mL)中之溶液。將混合物攪拌1 h並藉由過濾收集沈澱物。藉由製備型HPLC (Phenomenex Gemini-NX 150 mm × 30 mm × 5 µm, H₂ O/CH₃ CN (0.05%NH₄ OH)，在10 min內18-58%)純化固體以得到標題化合物 (65 mg, 19%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.23 (s, 0.6H), 7.07 (s, 0.4H), 3.54 - 3.46 (m, 3H), 3.37 - 3.33 (m, 2H), 3.04 (s, 3H), 2.41 (dt, 2H), 2.21-2.10 (m, 2H), 1.07 (d, 1.3H), 1.01 (d, 1.7H)；LC/MSm/z (M+H)⁺ = 388.8/390.8 (⁷⁹ Br,⁸¹ Br) Preparation 39 : (S)- N -(5- Amino -2- bromine -4- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use Br₂ (140 mg, 0.88 mmol) A solution of Preparation 38 (270 mg, 0.88 mmol) in AcOH (10 mL) was treated at 20°C. The mixture was stirred for 1 h and the precipitate was collected by filtration. By preparative HPLC (Phenomenex Gemini-NX 150 mm × 30 mm × 5 µm, H₂ O/CH₃ CN (0.05%NH₄ OH), 18-58% within 10 min) purify the solid to obtainTitle compound (65 mg, 19%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.23 (s, 0.6H), 7.07 (s, 0.4H), 3.54-3.46 (m, 3H), 3.37- 3.33 (m, 2H), 3.04 (s, 3H), 2.41 (dt, 2H), 2.21-2.10 (m, 2H), 1.07 (d, 1.3H), 1.01 (d, 1.7H); LC/MSm/z (M+H)⁺ = 388.8/390.8 (⁷⁹ Br,⁸¹ Br)

使用NH₄ Cl飽和水溶液(0.5 mL)及鐵粉(17.3 mg, 0.31 mmol)在20℃下處理39 (40 mg, 0.10 mmol)於EtOH (3 mL)中之溶液。將混合物加熱至70℃並保持1 h，且過濾。濃縮濾液並藉由製備型HPLC (Boston Prime C18, 150 × 30 mm × 5 µm；H₂ O/MeCN(0.05% NH₄ OH)，在10 min內16-39%)純化殘餘物以得到標題化合物 (5 mg, 10%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.75 (s, 0.3H), 6.72 (s, 0.7H), 6.58 (s, 0.7H), 6.47 (s, 0.3H), 4.91 (d, 2H), 4.82 (d, 2H), 3.55 - 3.46 (m, 4H), 3.09 (d, 2H), 2.96 (d, 3H), 1.06 (d, 1.3H), 1.01 (d, 1.7H)。LC/MSm/z (M+H) = 357.0/359.1 (⁷⁹ Br,⁸¹ Br) Preparation 40 : (S)- N -(4,5- Diamine group -2- Bromophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use NH₄ A solution of 39 (40 mg, 0.10 mmol) in EtOH (3 mL) was treated with saturated aqueous Cl (0.5 mL) and iron powder (17.3 mg, 0.31 mmol) at 20°C. The mixture was heated to 70°C for 1 h, and filtered. The filtrate was concentrated and subjected to preparative HPLC (Boston Prime C18, 150 × 30 mm × 5 µm; H₂ O/MeCN(0.05% NH₄ OH), within 10 min 16-39%) purify the residue to obtainTitle compound (5 mg, 10%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.75 (s, 0.3H), 6.72 (s, 0.7H), 6.58 (s, 0.7H), 6.47 (s, 0.3H), 4.91 (d, 2H), 4.82 (d, 2H), 3.55- 3.46 (m, 4H), 3.09 (d, 2H), 2.96 (d, 3H), 1.06 (d, 1.3H), 1.01 (d, 1.7H). LC/MSm/z (M+H) = 357.0/359.1 (⁷⁹ Br,⁸¹ Br)

使用BOC₂ O (187 g, 859 mmol)在20℃下處理5-氟-2-甲基-4-硝基苯胺(133 g, 781 mmol, 1當量)、DMAP (9.55 g, 78.1 mmol, 0.1當量)及i Pr₂ NEt (202 g, 1.56 mol, 272 mL, 2當量)於DCM (2 L)中之溶液。將混合物在20℃下攪拌16 h並濃縮。將殘餘物溶於EtOAc (3 L)中並使用NH₄ Cl飽和水溶液(1 L)、NaHCO₃ 飽和水溶液(1 L)及鹽水(1 L)依序洗滌。乾燥(Na₂ SO₄ )有機層，過濾並濃縮。使用MeOH (3 L)研磨殘餘物並藉由過濾收集固體以得到標題化合物 (90 g, 374 mmol)。 濃縮濾液並將殘餘物溶於MeOH (500 mL)中，且使用K₂ CO₃ (15.5 g)處理。將混合物在20℃下攪拌3 h。過濾混合物並使用MeOH沖洗固體。濃縮濾液並藉由層析(二氧化矽，EtOAc/PE = 0-10%)純化殘餘物以得到額外標題化合物 (45 g, 166 mmol)。 合併兩個批次以得到全部標題化合物 (135 g, 72%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.15 (d, 1H), 7.94 – 7.88 (m, 1H), 6.62 (s, 1H), 2.28 (s, 3H), 1.55 (s, 9H)。 Preparation 41 : (5- fluorine -2- methyl -4- Nitrophenyl ) Tert-butyl carbamate

Use BOC₂ O (187 g, 859 mmol) treated 5-fluoro-2-methyl-4-nitroaniline (133 g, 781 mmol, 1 equivalent), DMAP (9.55 g, 78.1 mmol, 0.1 equivalent) andi Pr₂ A solution of NEt (202 g, 1.56 mol, 272 mL, 2 equivalents) in DCM (2 L). The mixture was stirred at 20°C for 16 h and concentrated. The residue was dissolved in EtOAc (3 L) and used NH₄ Cl saturated aqueous solution (1 L), NaHCO₃ Saturated aqueous solution (1 L) and brine (1 L) were washed sequentially. Dry (Na₂ SO₄ ) Organic layer, filtered and concentrated. Use MeOH (3 L) to grind the residue and collect the solid by filtration to obtainTitle compound (90 g, 374 mmol). The filtrate was concentrated and the residue was dissolved in MeOH (500 mL), and K₂ CO₃ (15.5 g) Treatment. The mixture was stirred at 20°C for 3 h. The mixture was filtered and the solids were rinsed with MeOH. The filtrate was concentrated and the residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-10%) to obtain additionalTitle compound (45 g, 166 mmol). Combine the two batches to get allTitle compound (135 g, 72%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.15 (d, 1H), 7.94 – 7.88 (m, 1H), 6.62 (s, 1H), 2.28 (s, 3H), 1.55 (s, 9H).

使用KOtBu (81.9 g, 730 mmol)在0℃下處理製備物41 (131 g, 486 mmol)於THF (1.9 L)中之溶液且將混合物在0℃下攪拌1 h。在0℃下逐滴添加碘甲烷(61 mL, 980 mmol)。將所得混合物在20℃下攪拌16 h。使用NH₄ Cl飽和水溶液(500 mL)處理反應混合物並使用EtOAc (1 L)萃取。使用鹽水(500 mL)洗滌有機層，乾燥(Na₂ SO₄ )，並濃縮以得到標題化合物 (150 g, 95%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.95 (d, 1H), 7.07 (d, 1H), 3.17 (s, 3H), 2.26 (s, 3H), 1.40 (d, 9H)。 Preparation 42 : (5- fluorine -2- methyl -4- Nitrophenyl ) Tert-butyl carbamate

A solution of preparation 41 (131 g, 486 mmol) in THF (1.9 L) was treated with KOtBu (81.9 g, 730 mmol) at 0°C and the mixture was stirred at 0°C for 1 h. Add iodomethane (61 mL, 980 mmol) dropwise at 0°C. The resulting mixture was stirred at 20°C for 16 h. Use NH₄ The reaction mixture was treated with saturated aqueous Cl (500 mL) and extracted with EtOAc (1 L). The organic layer was washed with brine (500 mL) and dried (Na₂ SO₄ ) And condensed to getTitle compound (150 g, 95% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 7.95 (d, 1H), 7.07 (d, 1H), 3.17 (s, 3H), 2.26 (s, 3H), 1.40 (d, 9H).

將製備物42 (450 g, 1.38 mol, 1當量)於7 M NH₃ /MeOH (7 M, 5.5 L)中之溶液在58℃下加熱72 h。濃縮混合物。將殘餘物溶於EtOAc (2 L)中並使用鹽水(2 L)洗滌。乾燥(Na₂ SO₄ )有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-20%)純化粗產物以得到標題化合物 (295 g, 76%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.00 (s, 1H), 6.62 (s, 1H), 5.95 (s, 2H), 3.15 (s, 3H), 2.15 (d, 3H), 1.41 (s, 9H)；LC/MSm/z (M+H-第三丁基) = 225.8。 Preparation 43 : (5- Amino -2- methyl -4- Nitrophenyl )( methyl ) Tert-butyl carbamate

Prepare preparation 42 (450 g, 1.38 mol, 1 equivalent) in 7 M NH₃ The solution in /MeOH (7 M, 5.5 L) was heated at 58°C for 72 h. The mixture was concentrated. The residue was dissolved in EtOAc (2 L) and washed with brine (2 L). Dry (Na₂ SO₄ ) Organic layer, filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound (295 g, 76% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 8.00 (s, 1H), 6.62 (s, 1H), 5.95 (s, 2H), 3.15 (s, 3H), 2.15 (d, 3H), 1.41 (s, 9H); LC/MSm/z (M+H-tertiary butyl) = 225.8.

使用10% Pd/C (10 g)處理製備物43 (98 g, 349 mmol)於MeOH (1 L)中之溶液。將反應液在40℃及H₂ (3 atm)下攪拌24 h。過濾反應液並使用MeOH (3 × 500 mL)沖洗固體。濃縮濾液以得到標題化合物 (68.3 g, 78%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.32 (s, 1H), 6.27 (s, 1H), 4.37 (s, 2H), 4.29 (s, 2H), 2.96 (d, 3H), 1.89 (d, 3H), 1.44 (s, 3H), 1.28 (s, 6H；。LC/MSm/z (M+H-第三丁基) = 195.9。 Preparation 44 : (4,5- Diamine group -2- Methyl phenyl )( methyl ) Tert-butyl carbamate

A solution of Preparation 43 (98 g, 349 mmol) in MeOH (1 L) was treated with 10% Pd/C (10 g). Put the reaction solution at 40℃ and H₂ Stir at (3 atm) for 24 h. The reaction solution was filtered and MeOH (3 × 500 mL) was used to rinse the solids. Concentrate the filtrate to obtainTitle compound (68.3 g, 78%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.32 (s, 1H), 6.27 (s, 1H), 4.37 (s, 2H), 4.29 (s, 2H), 2.96 (d, 3H), 1.89 (d, 3H), 1.44 (s, 3H) , 1.28 (s, 6H; .LC/MSm/z (M+H-tertiary butyl) = 195.9.

使用9 (7.21 g, 23.5 mmol)及DMSO (4.6 g, 58.8 mmol)在室溫下處理製備物44 (5.53 g, 23.5 mmol)及Na₂ S₂ O₅ (2.24 g, 11.8 mmol)於DMF (124 mL)中之溶液。將混合物在110℃下加熱16 h。濃縮混合物。使用EtOAc (500 mL)稀釋殘餘物並使用3% LiCl水溶液(100 mL)洗滌。乾燥(MgSO₄ )有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-25%)純化粗產物以得到標題化合物 (10.8g, 86%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.46 (t, 1H), 7.38 (s, 1H), 5.53 - 5.42 (m, 2H), 3.63 (t, 2H), 3.40 (d, 1H), 3.26 - 3.11 (m, 5H), 2.77 (d, 1H), 2.33 (s, 3H), 1.56 (s, 3H), 1.36 - 1.30 (m, 9H), 1.18 (dd, 1H), 0.96 - 0.84 (m, 2H), 0.45 (dd, 1H), 0.28 (t, 1H), -0.02 (s, 9H)；LC/MSm/z (M+H)⁺ = 538.3。 Preparation 45 : methyl -(6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base ) Tert-butyl carbamate

Use 9 (7.21 g, 23.5 mmol) and DMSO (4.6 g, 58.8 mmol) at room temperature to treat preparation 44 (5.53 g, 23.5 mmol) and Na₂ S₂ O₅ (2.24 g, 11.8 mmol) in DMF (124 mL). The mixture was heated at 110°C for 16 h. The mixture was concentrated. The residue was diluted with EtOAc (500 mL) and washed with 3% aqueous LiCl (100 mL). Dry (MgSO₄ ) Organic layer, filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-25%) to obtainTitle compound (10.8g, 86%).¹ H NMR (400 MHz, CD₃ OD) δ 7.46 (t, 1H), 7.38 (s, 1H), 5.53-5.42 (m, 2H), 3.63 (t, 2H), 3.40 (d, 1H), 3.26-3.11 (m, 5H), 2.77 (d, 1H), 2.33 (s, 3H), 1.56 (s, 3H), 1.36-1.30 (m, 9H), 1.18 (dd, 1H), 0.96-0.84 (m, 2H), 0.45 (dd, 1H) ), 0.28 (t, 1H), -0.02 (s, 9H); LC/MSm/z (M+H)⁺ = 538.3.

使用ZnBr₂ (22.7 g, 101mmol)在0℃下處理製備物45 (10.86 g 20.2 mmol)於DCM (135 mL)中之溶液。將混合物逐漸升溫至室溫並攪拌16 h。將混合物傾倒至NaHCO₃ 飽和水溶液(200 mL)中並使用DCM (2 × 200 mL)萃取。乾燥(MgSO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-20%)純化粗產物以得到標題化合物 (7.54 g, 85.3%)。對掌性SFC (Chiralpak AS-3, 150 mm × 4.6 mm × 3 µm；CO₂ /含有0.05%i Pr₂ NEt之EtOH，在5.5 min內5 - 40%)；滯留時間= 2.93 min (97.2% ee)；¹ H NMR (400 MHz, CD₃ OD) δ 7.32 (s, 1H), 6.76 (s, 1H), 5.51 - 5.42 (m, 2H), 3.38 (t, 2H), 3.40 (d, 1H), 3.31 - 3.28 (m, 2H), 3.22 (s, 3H), 3.17 (m, 1H), 2.27 (s, 3H), 1.32 (s, 3H), 1.18 (m, 1H), 0.88 (m, 2H), 0.45 (dd, 1H), 0.28 (t, 1H), -0.02 (s, 9H)；LC/MSm/z (M+H)⁺ = 438.3。 Preparation 46 : N ,6- Dimethyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- amine

Use ZnBr₂ (22.7 g, 101 mmol) A solution of Preparation 45 (10.86 g 20.2 mmol) in DCM (135 mL) was treated at 0°C. The mixture was gradually warmed to room temperature and stirred for 16 h. Pour the mixture to NaHCO₃ Saturated aqueous solution (200 mL) and extracted with DCM (2×200 mL). Dry (MgSO₄ ) The combined organic layers are filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound (7.54 g, 85.3%). Opposite SFC (Chiralpak AS-3, 150 mm × 4.6 mm × 3 µm; CO₂ / Contains 0.05%i Pr₂ NEt EtOH, 5-40% within 5.5 min); retention time = 2.93 min (97.2% ee);¹ H NMR (400 MHz, CD₃ OD) δ 7.32 (s, 1H), 6.76 (s, 1H), 5.51-5.42 (m, 2H), 3.38 (t, 2H), 3.40 (d, 1H), 3.31-3.28 (m, 2H), 3.22 (s, 3H), 3.17 (m, 1H), 2.27 (s, 3H), 1.32 (s, 3H), 1.18 (m, 1H), 0.88 (m, 2H), 0.45 (dd, 1H), 0.28 ( t, 1H), -0.02 (s, 9H); LC/MSm/z (M+H)⁺ = 438.3.

使用Ac₂ O (250 mL)處理3-氟-4-硝基苯胺(20 g, 128.1 mmol)。將混合物在室溫下攪拌16 h且然後使用水(100 mL)稀釋。藉由過濾收集沈澱物。將固體溶解於EtOAc (100 mL)中，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 47 (23.0 g, 91%產率)。¹ H NMR (400 MHz, CD₃ OD) δ 8.09 (t, 1H), 7.86 (dd, 1H), 7.38 (dt, 1H), 2.17 (s, 3H)。 Preparation 47 : N -(3- fluorine -4- Nitrophenyl ) Acetamide

Use Ac₂ Treat 3-fluoro-4-nitroaniline (20 g, 128.1 mmol) with O (250 mL). The mixture was stirred at room temperature for 16 h and then diluted with water (100 mL). The precipitate was collected by filtration. The solid was dissolved in EtOAc (100 mL) and dried (Na₂ SO₄ ), filtered and concentrated to getTitle compound 47 (23.0 g, 91% yield).¹ H NMR (400 MHz, CD₃ OD) δ 8.09 (t, 1H), 7.86 (dd, 1H), 7.38 (dt, 1H), 2.17 (s, 3H).

使用NaH (6.96 g, 174 mmol)在0℃下處理製備物47 (23.0 g, 116.1 mmol)於DMF (300 mL)中之溶液並攪拌20 min。添加碘甲烷(33.0 g, 232 mmol)且將混合物攪拌2 h。使用水(100 mL)處理混合物並使用10% MeOH/EtOAc (2 × 200 mL)萃取所得混合物。收集萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 20- 50%)純化粗產物以得到標題化合物 (16.0 g, 65%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.13 (t, 1H), 7.25 - 7.15 (m, 2H), 3.35 (s, 3H), 2.10 (s, 3H) Preparation 48. N -(3- fluorine -4- Nitrophenyl )- N- Methyl acetamide

A solution of Preparation 47 (23.0 g, 116.1 mmol) in DMF (300 mL) was treated with NaH (6.96 g, 174 mmol) at 0°C and stirred for 20 min. Iodomethane (33.0 g, 232 mmol) was added and the mixture was stirred for 2 h. The mixture was treated with water (100 mL) and the resulting mixture was extracted with 10% MeOH/EtOAc (2×200 mL). Collect the extract and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 20-50%) to obtainTitle compound (16.0 g, 65% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 8.13 (t, 1H), 7.25-7.15 (m, 2H), 3.35 (s, 3H), 2.10 (s, 3H)

使用濃NH₄ OH (13.2 g, 377 mmol)在室溫下處理製備物48 (16.0 g, 75.4 mmol)於EtOH (200 mL)中之溶液。將混合物在50℃下加熱3天並濃縮混合物。藉由層析(二氧化矽，EtOAc/PE = 40-80%)純化殘餘物以得到標題化合物 (7.5 g, 48%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.17 (d, 1H), 6.66 (d, 1H), 6.54 (dd, 1H), 6.18 (s, 2H), 3.27 (s, 3H), 2.02 (s, 3H)；LC/MSm/z (M+H)⁺ = 210.3。 Preparation 49 : N -(3- Amino -4- Nitrophenyl )- N- Methyl acetamide

Use concentrated NH₄ A solution of Preparation 48 (16.0 g, 75.4 mmol) in EtOH (200 mL) was treated with OH (13.2 g, 377 mmol) at room temperature. The mixture was heated at 50°C for 3 days and the mixture was concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 40-80%) to obtainTitle compound (7.5 g, 48% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 8.17 (d, 1H), 6.66 (d, 1H), 6.54 (dd, 1H), 6.18 (s, 2H), 3.27 (s, 3H), 2.02 (s, 3H); LC/MSm/z (M+H)⁺ = 210.3.

使用10% Pd/C (1.5 g)處理製備物49 (6.5 g, 31.1 mmol)於MeOH (40 mL)中之溶液。將混合物在20℃及H₂ (2 atm)下攪拌3小時。過濾混合物並使用MeOH (2 × 50 mL)沖洗固體。濃縮濾液以得到標題化合物 (5.38 g, 96%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.71 - 6.64 (m, 1H), 6.50 (d, 2H), 3.46 (d, 4H), 3.19 (s, 3H), 1.87 (s, 3H)；LC/MSm/z (M+H)⁺ = 180.3。 Preparation 50 : N -(3,4- Diaminophenyl )- N- Methyl acetamide

A solution of Preparation 49 (6.5 g, 31.1 mmol) in MeOH (40 mL) was treated with 10% Pd/C (1.5 g). Put the mixture at 20℃ and H₂ (2 atm) and stir for 3 hours. The mixture was filtered and MeOH (2×50 mL) was used to rinse the solids. Concentrate the filtrate to obtainTitle compound (5.38 g, 96% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 6.71-6.64 (m, 1H), 6.50 (d, 2H), 3.46 (d, 4H), 3.19 (s, 3H), 1.87 (s, 3H); LC/MSm/z (M+H)⁺ = 180.3.

使用N-甲基乙醯胺(11.5 g, 158 mmol)、Cs₂ CO₃ (68.5 g, 210 mmol)、Pd₂ (dba)₃ (9.62 g, 10.5 mmol)、XantPhos (6.08 g, 10.5 mmol)及三氟甲磺酸鋁(III) (9.96 g, 21 mmol)在25℃及N₂ 下處理5-溴-1,3-二氟-2-硝基苯(25.0 g, 105.0 mmol)在PhCH₃ (250 mL)中之溶液。將混合物在100℃下加熱15 h。藉由過濾去除固體並濃縮濾液。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化殘餘物以得到標題化合物 (8.75 g, 36%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.10 - 6.99 (m, 2H), 3.34 (s, 3H), 2.15 (s, 3H)；LC/MSm/z (M+H)⁺ = 230.9。 Preparation 51 : N -(3,5- Difluoro -4- Nitrophenyl )- N- Methyl acetamide

Use N-methylacetamide (11.5 g, 158 mmol), Cs₂ CO₃ (68.5 g, 210 mmol), Pd₂ (dba)₃ (9.62 g, 10.5 mmol), XantPhos (6.08 g, 10.5 mmol) and aluminum(III) trifluoromethanesulfonate (9.96 g, 21 mmol) at 25℃ and N₂ Down treatment 5-bromo-1,3-difluoro-2-nitrobenzene (25.0 g, 105.0 mmol) in PhCH₃ (250 mL) in the solution. The mixture was heated at 100°C for 15 h. The solids were removed by filtration and the filtrate was concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (8.75 g, 36%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.10-6.99 (m, 2H), 3.34 (s, 3H), 2.15 (s, 3H); LC/MSm/z (M+H)⁺ = 230.9.

使用濃NH₄ OH (24 mL)處理製備物51 (8.75 g, 38.0 mmol)於EtOH (95 mL)中之溶液。將混合物在室溫下攪拌16 h並使用水(120 mL)處理。使用EtOAc (2 × 80 mL)萃取混合物。使用鹽水洗滌合併之有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 (5.70 g, 66%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.17 (s, 2H), 6.69 (t, 1H), 6.62 (dd, 1H), 3.15 (s, 3H), 1.99 (s, 3H)。LC/MSm/z (M+H)⁺ = 227.9。 Preparation 52 : N -(3- Amino -5- fluorine -4- Nitrophenyl )- N- Methyl acetamide

Use concentrated NH₄ A solution of Preparation 51 (8.75 g, 38.0 mmol) in EtOH (95 mL) was treated with OH (24 mL). The mixture was stirred at room temperature for 16 h and treated with water (120 mL). The mixture was extracted with EtOAc (2×80 mL). The combined organic extracts were washed with brine and dried (Na₂ SO₄ ), filtered and concentrated to getTitle compound (5.70 g, 66%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.17 (s, 2H), 6.69 (t, 1H), 6.62 (dd, 1H), 3.15 (s, 3H), 1.99 (s, 3H). LC/MSm/z (M+H)⁺ = 227.9.

使用10% Pd/C (700 mg)處理製備物52 (5.70 g, 25.1 mmol)於EtOH (150 mL)中之溶液。將混合物在H₂ (1 atm)及25℃下攪拌24 h。過濾混合物並使用EtOH沖洗固體。濃縮濾液以得到標題化合物 (4.6 g, 93%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.32 (dd, 1H), 6.24 (dd, 1H), 5.01 (s, 2H), 4.52 (s, 2H), 3.02 (s, 3H), 1.74 (s, 3H)；LC/MSm/z (M+H)⁺ = 198.1。 Preparation 53 : N -(3,4- Diamine group -5- Fluorophenyl )- N- Methyl acetamide

A solution of Preparation 52 (5.70 g, 25.1 mmol) in EtOH (150 mL) was treated with 10% Pd/C (700 mg). Put the mixture in H₂ (1 atm) and stirring at 25°C for 24 h. The mixture was filtered and EtOH was used to rinse the solids. Concentrate the filtrate to obtainTitle compound (4.6 g, 93%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.32 (dd, 1H), 6.24 (dd, 1H), 5.01 (s, 2H), 4.52 (s, 2H), 3.02 (s, 3H), 1.74 (s, 3H); LC/MSm/z (M+H)⁺ = 198.1.

使用Na₂ S₂ O₅ (2.79 g, 14.7 mmol)、9 (9.0 g, 29.4 mmol)及DMSO (5.74 g, 73.4 mmol)處理製備物50 (5.26 g, 29.4 mmol)於DMF (147 mL)中之溶液。將混合物在110℃下加熱6 h並傾倒至3% LiCl水溶液(250 mL)中。使用EtOAc (3 × 100 mL)萃取將混合物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0- 100%)純化粗產物以得到標題化合物 (13 g, 95%產率)。¹ H NMR (400 MHz, DMSO-d ₆ )旋轉異構體混合物δ 12.83 (s, 1H), 7.96 (s, 1H), 7.67 (d, 0.5 x H), 7.59 (s, 0.5 x H), 7.48 (d, 0.5 x H), 7.33 (s, 0.5 x H), 7.16 - 7.06 (m, 1H), 5.55 - 5.28 (m, 2H), 3.23-3.12 (m, 3 H), 3.07 - 2.96 (m, 1H), 2.89 (s, 3H), 2.76-2.64 (m, 4 H), 1.26 (s, 3H), 1.22 - 1.01 (m, 1H), 0.84 (dd, 2H), 0.41 (dd, 1H), 0.18 - 0.15 (m, 1H), -0.06 (s, 9H)；LC/MSm/z (M+H)⁺ = 466.2。 Preparation 54 : N - methyl -N -(2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base ) Acetamide

Use Na₂ S₂ O₅ A solution of Preparation 50 (5.26 g, 29.4 mmol) in DMF (147 mL) was treated with (2.79 g, 14.7 mmol), 9 (9.0 g, 29.4 mmol) and DMSO (5.74 g, 73.4 mmol). The mixture was heated at 110 °C for 6 h and poured into a 3% LiCl aqueous solution (250 mL). The mixture was extracted with EtOAc (3 × 100 mL) and dried (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (13 g, 95% yield).¹ H NMR (400 MHz, DMSO-d ₆ ) Rotamer mixture δ 12.83 (s, 1H), 7.96 (s, 1H), 7.67 (d, 0.5 x H), 7.59 (s, 0.5 x H), 7.48 (d, 0.5 x H), 7.33 ( s, 0.5 x H), 7.16-7.06 (m, 1H), 5.55-5.28 (m, 2H), 3.23-3.12 (m, 3 H), 3.07-2.96 (m, 1H), 2.89 (s, 3H) , 2.76-2.64 (m, 4 H), 1.26 (s, 3H), 1.22-1.01 (m, 1H), 0.84 (dd, 2H), 0.41 (dd, 1H), 0.18-0.15 (m, 1H), -0.06 (s, 9H); LC/MSm/z (M+H)⁺ = 466.2.

使用5N NaOH (11.6 mL)在室溫下處理製備物54 (2.70 g, 5.8 mmol)於EtOH (22 mL)中之溶液。將反應液在90℃下加熱16小時。將水(150 mL)添加至混合物中且使用EtOAc (2 × 150 mL)萃取混合物。使用鹽水(50 mL)洗滌合併之有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 50-100%)純化粗產物以得到標題化合物 55 (93 mg, 38%產率)。¹ H NMR (400 MHz, CD₃ OD) δ 7.39 (d, 1H), 6.78 - 6.73 (m, 1H), 6.68 (dd, 1H), 5.47 - 5.39 (m, 2H), 3.66 - 3.50 (m, 2H), 3.37-3.31 (m, 1 H), 3.22 - 3.04 (m, 2H), 2.82 (s, 3H), 2.75 (d, 1H), 1.30 (s, 3H), 1.16 (dt, 1H), 0.88 (td, 2H), 0.43 (dd, 1H), 0.25 (t, 1H), -0.03 (s, 9H)；LC/MSm/z (M+H)⁺ = 424.2。 Preparation 55 : N - methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- amine

A solution of Preparation 54 (2.70 g, 5.8 mmol) in EtOH (22 mL) was treated with 5N NaOH (11.6 mL) at room temperature. The reaction solution was heated at 90°C for 16 hours. Water (150 mL) was added to the mixture and the mixture was extracted with EtOAc (2×150 mL). Wash the combined organic extracts with brine (50 mL) and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 50-100%) to obtainTitle compound 55 (93 mg, 38% yield).¹ H NMR (400 MHz, CD₃ OD) δ 7.39 (d, 1H), 6.78-6.73 (m, 1H), 6.68 (dd, 1H), 5.47-5.39 (m, 2H), 3.66-3.50 (m, 2H), 3.37-3.31 (m, 1 H), 3.22-3.04 (m, 2H), 2.82 (s, 3H), 2.75 (d, 1H), 1.30 (s, 3H), 1.16 (dt, 1H), 0.88 (td, 2H), 0.43 ( dd, 1H), 0.25 (t, 1H), -0.03 (s, 9H); LC/MSm/z (M+H)⁺ = 424.2.

使用製備物53 (4.20 g, 21.3 mmol)、Na₂ S₂ O₅ (2.02 g, 10.6 mmol)及DMSO (4.16 g, 53.2 mmol)在25℃下處理製備物9 (6.53 g, 21.3 mmol)於DMF (106 mL)中之溶液。將混合物在110℃下加熱16 h並使用3% LiCl水溶液(50 mL)稀釋。使用EtOAc (2 × 50 mL)萃取混合物。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-75%)純化粗產物以得到標題化合物 (7.55 g, 67%)。¹ H NMR (400 MHz, CDCl₃ ) δ 9.99 (d, 1H), 7.45 (d, 0.5H), 7.12 - 7.03 (m, 0.5H), 6.87 - 6.71 (m, 1H), 5.40 (qd, 2H), 3.62 - 3.45 (m, 3H), 3.30 (s, 3H), 3.23 - 3.05 (m, 2H), 2.75 (d, 1H), 1.90 (s, 3H), 1.29 (s, 3H), 1.16 (s, 1H), 0.91 (ddd, 2H), 0.43 (dt, 1H), 0.27 (d, 1H), -0.02 (d, 9H)；LC/MSm/z (M+H)⁺ = 484.4。 Preparation 56 : N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- Methyl acetamide

Use preparation 53 (4.20 g, 21.3 mmol), Na₂ S₂ O₅ A solution of Preparation 9 (6.53 g, 21.3 mmol) in DMF (106 mL) was treated with DMSO (4.16 g, 53.2 mmol) and DMSO (4.16 g, 53.2 mmol) at 25°C. The mixture was heated at 110°C for 16 h and diluted with 3% aqueous LiCl (50 mL). The mixture was extracted with EtOAc (2×50 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-75%) to obtainTitle compound (7.55 g, 67%).¹ H NMR (400 MHz, CDCl₃ ) δ 9.99 (d, 1H), 7.45 (d, 0.5H), 7.12-7.03 (m, 0.5H), 6.87-6.71 (m, 1H), 5.40 (qd, 2H), 3.62-3.45 (m, 3H) ), 3.30 (s, 3H), 3.23-3.05 (m, 2H), 2.75 (d, 1H), 1.90 (s, 3H), 1.29 (s, 3H), 1.16 (s, 1H), 0.91 (ddd, 2H), 0.43 (dt, 1H), 0.27 (d, 1H), -0.02 (d, 9H); LC/MSm/z (M+H)⁺ = 484.4.

使用5N NaOH (26.9 mL, 134 mmol)處理製備物56 (6.50 g, 13.44 mmol)於EtOH (51.7 mL)中之溶液。將反應混合物在90℃下加熱46 h。添加水(200 mL)並使用EtOAc (2 × 200 mL)萃取混合物。合併有機萃取物，使用鹽水(50 mL)洗滌，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化粗產物以得到標題化合物 (5.2 g, 75.9%)。¹ H NMR (400 MHz, CD₃ OD) δ 6.47 (s, 1H), 6.38 (dd, 1H), 5.48 - 5.38 (m, 2H), 3.60 (t, 2H), 3.37-3.30 (m, 1H), 3.21 - 3.08 (m, 2H), 2.83-2.72 (m, 1H), 2.80 (s, 3H), 1.29 (s, 3H), 1.15 (dt, 1H), 0.88 (td, 2H), 0.42 (dd, 1H), 0.25 (t, 1H), -0.03 (s, 9H)；LC/MSm/z (M+H)⁺ = 442.2。 Preparation 57 : 7- fluorine -N- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- amine

A solution of Preparation 56 (6.50 g, 13.44 mmol) in EtOH (51.7 mL) was treated with 5N NaOH (26.9 mL, 134 mmol). The reaction mixture was heated at 90 °C for 46 h. Water (200 mL) was added and the mixture was extracted with EtOAc (2×200 mL). Combine the organic extracts, wash with brine (50 mL), and dry (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-50%) to obtainTitle compound (5.2 g, 75.9%).¹ H NMR (400 MHz, CD₃ OD) δ 6.47 (s, 1H), 6.38 (dd, 1H), 5.48-5.38 (m, 2H), 3.60 (t, 2H), 3.37-3.30 (m, 1H), 3.21-3.08 (m, 2H) , 2.83-2.72 (m, 1H), 2.80 (s, 3H), 1.29 (s, 3H), 1.15 (dt, 1H), 0.88 (td, 2H), 0.42 (dd, 1H), 0.25 (t, 1H) ), -0.03 (s, 9H); LC/MSm/z (M+H)⁺ = 442.2.

在15℃下，將5-氟-2-甲基-4-硝基苯胺(9.5 g, 56 mmol)逐份添加至Ac₂ O (100 mL)中。將反應混合物在15℃下攪拌36 h。藉由過濾收集固體並使用水(3 × 50 mL)沖洗。乾燥固體以得到標題化合物 58 (6.3 g, 53%)。 使用EtOAc (100 mL)萃取濾液。使用水(2 × 100 mL)、Na₂ HCO₃ 飽和水溶液(3 × 100 mL)洗滌有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗產物以得到額外標題化合物 58 (4 g, 34%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.34 (d, 1H), 7.94 (d, 1H), 7.17 (s, 1H), 2.32 (s, 3H), 2.28 (s, 3H)。 Preparation 58 : N -(5- fluorine -2- methyl -4- Nitrophenyl ) Acetamide

At 15°C, 5-fluoro-2-methyl-4-nitroaniline (9.5 g, 56 mmol) was added portionwise to Ac₂ O (100 mL). The reaction mixture was stirred at 15°C for 36 h. Collect the solid by filtration and rinse with water (3 × 50 mL). Dry the solid to getTitle compound 58 (6.3 g, 53%). The filtrate was extracted with EtOAc (100 mL). Use water (2 × 100 mL), Na₂ HCO₃ The organic layer was washed with saturated aqueous solution (3 × 100 mL) and dried (Na₂ SO₄ ), filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtain additionalTitle compound 58 (4 g, 34%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.34 (d, 1H), 7.94 (d, 1H), 7.17 (s, 1H), 2.32 (s, 3H), 2.28 (s, 3H).

使用KOtBu (48.2 mL, 1M THF)在0℃下處理製備物58 (9.3 g, 43.8 mmol)於THF (220 mL)中之溶液。將混合物在0℃下攪拌1 h且然後使用碘甲烷(6.84 g, 48.2 mmol)於THF (20 mL)中之溶液進行處理。將混合物升溫至15℃並攪拌16 h。使用NH₄ Cl飽和水溶液(50 mL)處理混合物。使用EtOAc (2 × 50 mL)萃取混合物。使用鹽水洗滌合併之有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 20-50%)純化粗產物以得到標題化合物 59 (9.4 g, 95%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.04 (d, 1H), 7.13 (d, 1H), 3.18 (s, 3H), 2.30 (s, 3H), 1.82 (s, 3H)；LC/MSm/z (M+H)⁺ = 226.9。 Preparation 59 : N -(5- fluorine -2- methyl -4- Nitrophenyl )- N- Methyl acetamide

A solution of Preparation 58 (9.3 g, 43.8 mmol) in THF (220 mL) was treated with KOtBu (48.2 mL, 1M THF) at 0°C. The mixture was stirred at 0°C for 1 h and then treated with a solution of methyl iodide (6.84 g, 48.2 mmol) in THF (20 mL). The mixture was warmed to 15°C and stirred for 16 h. Use NH₄ The mixture was treated with saturated aqueous Cl (50 mL). The mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine and dried (Na₂ SO₄ ), filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 20-50%) to obtainTitle compound 59 (9.4 g, 95%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.04 (d, 1H), 7.13 (d, 1H), 3.18 (s, 3H), 2.30 (s, 3H), 1.82 (s, 3H); LC/MSm/z (M+H)⁺ = 226.9.

使用濃NH₄ OH (200 mL)在15℃下處理製備物59 (10.3 g, 45.5 mmol)於EtOH (200 mL)中之溶液。在50℃下加熱混合物並攪拌40 h。在減壓下去除EtOH且過濾懸浮液以收集固體。使用水洗滌固體並乾燥以提供標題化合物 (9 g, 89%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.07 (s, 1H), 6.65 (s, 1H), 6.05 (s, 2H), 3.15 (s, 3H), 2.15 (s, 3H), 1.82 (s, 3H)；LC/MSm/z (M+H)⁺ = 224.1。 Preparation 60 : N -(5- Amino -2- methyl -4- Nitrophenyl )- N- Methyl acetamide

Use concentrated NH₄ A solution of Preparation 59 (10.3 g, 45.5 mmol) in EtOH (200 mL) was treated with OH (200 mL) at 15°C. The mixture was heated at 50°C and stirred for 40 h. The EtOH was removed under reduced pressure and the suspension was filtered to collect the solid. Use water to wash the solids and dry to provideTitle compound (9 g, 89%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.07 (s, 1H), 6.65 (s, 1H), 6.05 (s, 2H), 3.15 (s, 3H), 2.15 (s, 3H), 1.82 (s, 3H); LC/MSm/z (M+H)⁺ = 224.1.

使用10% Pd/C (1.3 g)處理製備物60 (8 g, 35.8 mmol)於EtOH (10 mL)中之溶液。使用N₂ 將混合物脫氣並使用H₂ 回填三次。將反應混合物在15℃及H₂ (1 atm)下攪拌16 h。過濾混合物並濃縮濾液以得到標題化合物 (7.7 g, 99%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.57 (s, 1H), 6.46 (s, 1H), 3.40 (s, 4H), 3.12 (s, 3H), 2.05 (s, 3H), 1.78 (s, 3H)；LC/MSm/z (M+H)⁺ = 194.3。 Preparation 61 : N -(4,5- Diamine group -2- Methyl phenyl )- N- Methyl acetamide

A solution of Preparation 60 (8 g, 35.8 mmol) in EtOH (10 mL) was treated with 10% Pd/C (1.3 g). Use N₂ Degas the mixture and use H₂ Backfill three times. Put the reaction mixture at 15℃ and H₂ (1 atm) and stir for 16 h. Filter the mixture and concentrate the filtrate to obtainTitle compound (7.7 g, 99%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.57 (s, 1H), 6.46 (s, 1H), 3.40 (s, 4H), 3.12 (s, 3H), 2.05 (s, 3H), 1.78 (s, 3H); LC/MSm/z (M+H)⁺ = 194.3.

混合製備物61 (4 g, 20.7 mmol)及Na₂ S₂ O₅ (1.97 g, 10.3 mmol)與製備物9 (6.84 g, 22.3 mmol)於DMF (100 mL)及DMSO (3.7 mL)中之溶液。將混合物在110℃下加熱16 h。將混合物冷卻至室溫且添加3% LiCl水溶液(150 mL)。藉由過濾收集所得固體，使用水洗滌並乾燥以得到標題化合物 (7.9 g, 80%)。¹ H NMR (400 MHz, CDCl₃ ) δ 9.88 (s, 1H), 7.58 (s, 1H), 7.31 (s, 1H), 5.50 - 5.26 (m, 2H), 3.55 (t, 3H), 3.23 (s, 3H), 3.20 - 3.05 (m, 2H), 2.74 (d, 1H), 2.32 (s, 3H), 1.79 (s, 3H), 1.29 (s, 3H), 1.16 (dt, 1H), 0.90 (dd, 2H), 0.42 (dd, 1H), 0.26 (t, 1H), -0.03 (s, 9H)；LC/MSm/z (M+H)⁺ = 480.4。 Preparation 62 : N - methyl -N -(6- methyl -2-((4a S ,5a R )-5a- methyl -1-((2- ( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base ) Acetamide

Mixed preparation 61 (4 g, 20.7 mmol) and Na₂ S₂ O₅ (1.97 g, 10.3 mmol) and Preparation 9 (6.84 g, 22.3 mmol) in DMF (100 mL) and DMSO (3.7 mL). The mixture was heated at 110°C for 16 h. The mixture was cooled to room temperature and 3% LiCl aqueous solution (150 mL) was added. The obtained solid was collected by filtration, washed with water and dried to obtainTitle compound (7.9 g, 80%).¹ H NMR (400 MHz, CDCl₃ ) δ 9.88 (s, 1H), 7.58 (s, 1H), 7.31 (s, 1H), 5.50-5.26 (m, 2H), 3.55 (t, 3H), 3.23 (s, 3H), 3.20-3.05 ( m, 2H), 2.74 (d, 1H), 2.32 (s, 3H), 1.79 (s, 3H), 1.29 (s, 3H), 1.16 (dt, 1H), 0.90 (dd, 2H), 0.42 (dd , 1H), 0.26 (t, 1H), -0.03 (s, 9H); LC/MSm/z (M+H)⁺ = 480.4.

在攪拌及15℃下，將4-氟-2-甲基-5-硝基苯胺(16.7 g, 98.2 mmol)添加至Ac₂ O (200 mL)中，且將混合物在15℃下攪拌16 h。使用水(300 mL)處理混合物並使用EtOAc (300 mL)萃取。使用Na₂ CO₃ 飽和水溶液(2 × 150 mL)及鹽水(100 mL)洗滌有機層。乾燥(Na₂ SO₄ )有機層，過濾並濃縮。使用EtOAc/PE (v/v=1:5, 100 mL)研磨殘餘物。藉由過濾收集所得固體並乾燥以得到標題化合物 (15 g, 72%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.52 (d, 1H), 7.13 (br d, 2H), 2.35 (s, 3H), 2.25 (s, 3H) Preparation 63 : N -(4- fluorine -2- methyl -5- Nitrophenyl ) Acetamide

Under stirring and 15°C, 4-fluoro-2-methyl-5-nitroaniline (16.7 g, 98.2 mmol) was added to Ac₂ O (200 mL), and the mixture was stirred at 15 °C for 16 h. The mixture was treated with water (300 mL) and extracted with EtOAc (300 mL). Use Na₂ CO₃ The organic layer was washed with saturated aqueous solution (2×150 mL) and brine (100 mL). Dry (Na₂ SO₄ ) Organic layer, filtered and concentrated. The residue was triturated with EtOAc/PE (v/v=1:5, 100 mL). The resulting solid was collected by filtration and dried to obtainTitle compound (15 g, 72%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.52 (d, 1H), 7.13 (br d, 2H), 2.35 (s, 3H), 2.25 (s, 3H)

使用濃NH₄ OH (198 g)在30℃下處理製備物63 (15 g, 70.7 mmol)於EtOH (300 mL)中之溶液且將混合物在50℃下攪拌16 h。添加額外濃NH₄ OH (140 g)且將混合物在50℃下攪拌16 h。添加額外濃NH₄ OH (46 g)且將混合物在60℃下攪拌16 h。濃縮混合物並藉由過濾收集固體。使用水(3 × 10 mL)洗滌固體並乾燥以提供標題化合物 (14.0 g, 95%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.97 (s, 1H), 6.81 (s, 1H), 2.19 (s, 3H), 2.13 (s, 3H) Preparation 64 : N -(4- Amino -2- methyl -5- Nitrophenyl ) Acetamide

Use concentrated NH₄ A solution of Preparation 63 (15 g, 70.7 mmol) in EtOH (300 mL) was treated with OH (198 g) at 30°C and the mixture was stirred at 50°C for 16 h. Add extra concentrated NH₄ OH (140 g) and the mixture was stirred at 50 °C for 16 h. Add extra concentrated NH₄ OH (46 g) and the mixture was stirred at 60 °C for 16 h. The mixture was concentrated and the solid was collected by filtration. Wash the solid with water (3 × 10 mL) and dry to provideTitle compound (14.0 g, 95%).¹ H NMR (400 MHz, CD₃ OD) δ 7.97 (s, 1H), 6.81 (s, 1H), 2.19 (s, 3H), 2.13 (s, 3H)

將製備物64 (2.50 g, 11.95 mmol)於EtOH (50 mL)中之懸浮液添加至10% Pd/C (500 mg)於EtOH (10 mL)中之懸浮液中。將混合物脫氣並使用H₂ 再填充三次，且將反應混合物在15℃及H₂ (1 atm)下攪拌16 h。過濾混合物並濃縮濾液以提供標題化合物 65 (2.2 g, 103%)。LC/MSm/z (M+H)⁺ = 180.1。 Preparation 63 : N -(4,5- Diamine group -2- Methyl phenyl ) Acetamide

A suspension of preparation 64 (2.50 g, 11.95 mmol) in EtOH (50 mL) was added to a suspension of 10% Pd/C (500 mg) in EtOH (10 mL). Degas the mixture and use H₂ Fill it three more times, and place the reaction mixture at 15°C and H₂ (1 atm) and stir for 16 h. Filter the mixture and concentrate the filtrate to provideTitle compound 65 (2.2 g, 103%). LC/MSm/z (M+H)⁺ = 180.1.

使用Na₂ S₂ O₅ (1.17 g, 6.14 mmol)、DMSO (2.18 mL, 30.7 mmol)及於DMF (20 mL)中之9 (3.76 g, 12.3 mmol)處理製備物65 (2.20 g, 12.28 mmol)於DMF (40 mL)中之溶液。將混合物在100℃下攪拌16 h。濃縮混合物並藉由層析(二氧化矽，EtOAc/PE = 0-100%，然後MeOH/DCM 0-10%)純化粗產物以提供標題化合物 66 (5.3 g, 92%)。LC/MSm/z (M+H)⁺ = 466.2。 Preparation 66 : N -(6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base ) Acetamide

Use Na₂ S₂ O₅ (1.17 g, 6.14 mmol), DMSO (2.18 mL, 30.7 mmol) and 9 (3.76 g, 12.3 mmol) in DMF (20 mL). Preparation 65 (2.20 g, 12.28 mmol) in DMF (40 mL) In the solution. The mixture was stirred at 100°C for 16 h. The mixture was concentrated and the crude product was purified by chromatography (silica dioxide, EtOAc/PE=0-100%, then MeOH/DCM 0-10%) to provideTitle compound 66 (5.3 g, 92%). LC/MSm/z (M+H)⁺ = 466.2.

使用製備物66 (2 g, 4.3 mmol)於THF (10 mL)中之溶液在0℃下處理LiAlH₄ (326 mg, 8.59 mmol)於THF (33 mL)中之懸浮液並在20℃下攪拌72 h。使用Na₂ SO₄ .H₂ O處理混合物，隨後使用MgSO₄ (4g)處理。將混合物攪拌30 min。使用EtOAc (20 mL)稀釋混合物並過濾。濃縮濾液且藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化殘餘物以得到標題化合物 (1.03 g, 53%)。¹ H NMR (400 MHz, CDCl₃ ) δ 9.55 (s, 1H), 7.51 (s, 1H), 7.10 (d, 1H), 6.57 (s, 1H), 5.43 - 5.27 (m, 2H), 3.60 - 3.50 (m, 3H), 3.28 - 3.13 (m, 3H), 3.09 (d, 1H), 2.72 (d, 1H), 2.25 (s, 3H), 1.35 (t, 3H), 1.28 (s, 3H), 1.14 (dt, 1H), 0.96 - 0.84 (m, 2H), 0.39 (dd, 1H), 0.28 (t, 1H), -0.03 (s, 9H)；LC/MSm/z (M+H)⁺ = 452.3。 Preparation 67 : N - Ethyl -6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- amine

A solution of preparation 66 (2 g, 4.3 mmol) in THF (10 mL) was used to treat LiAlH at 0°C₄ (326 mg, 8.59 mmol) in THF (33 mL) and stirred at 20°C for 72 h. Use Na₂ SO₄ .H₂ O treatment of the mixture, followed by MgSO₄ (4g) Treatment. The mixture was stirred for 30 min. The mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica dioxide, EtOAc/PE=0-50%) to obtainTitle compound (1.03 g, 53%).¹ H NMR (400 MHz, CDCl₃ ) δ 9.55 (s, 1H), 7.51 (s, 1H), 7.10 (d, 1H), 6.57 (s, 1H), 5.43-5.27 (m, 2H), 3.60-3.50 (m, 3H), 3.28- 3.13 (m, 3H), 3.09 (d, 1H), 2.72 (d, 1H), 2.25 (s, 3H), 1.35 (t, 3H), 1.28 (s, 3H), 1.14 (dt, 1H), 0.96 -0.84 (m, 2H), 0.39 (dd, 1H), 0.28 (t, 1H), -0.03 (s, 9H); LC/MSm/z (M+H)⁺ = 452.3.

使用NaOH (468 mg, 11.7 mmol)在20℃下處理製備物15 (1.0 g, 3.90 mmol)於MeOH (12 mL)及水(2.0 mL)中之溶液。在32 h之後，濃縮混合物並使用H₂ O (10 mL)稀釋殘餘物，且使用1M HCl將pH調節至4-5。過濾所得懸浮液以收集固體。乾燥固體以得到標題化合物 (900 mg, 100%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (bs, 2H), 3.16 (d, 1H), 3.03-2.97 (m, 3H), 2.76 (dd, 1H), 1.75 (d, 1H), 1.33 (d, 3H).；LC/MSm/z (M+H)⁺ = 228.8。 Preparation 68 : (4aS,5aR)-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Formic acid

A solution of Preparation 15 (1.0 g, 3.90 mmol) in MeOH (12 mL) and water (2.0 mL) was treated with NaOH (468 mg, 11.7 mmol) at 20°C. After 32 h, concentrate the mixture and use H₂ The residue was diluted with O (10 mL), and the pH was adjusted to 4-5 using 1M HCl. The resulting suspension was filtered to collect the solids. Dry the solid to getTitle compound (900 mg, 100%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (bs, 2H), 3.16 (d, 1H), 3.03-2.97 (m, 3H), 2.76 (dd, 1H), 1.75 (d, 1H), 1.33 (d, 3H).; LC/MSm/z (M+H)⁺ = 228.8.

使用5-溴-3-氟苯-1,2-二胺(358 mg, 1.75 mmol)及Na₂ S₂ O₅ (380 mg, 2.00 mmol)在室溫下處理製備物9 (510 mg, 1.66 mmol)於DMF (20.8 mL)中之溶液。密封小瓶並在150℃下於微波反應器中加熱2 h。將混合物傾倒至3% LiCl水溶液(40 mL)中並使用EtOAc (2 × 40 mL)萃取混合物。乾燥(Na₂ SO₄ )有機萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0- 25%)純化粗產物以得到標題化合物 (815 g, 98%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.50 (s, 1H), 7.23 - 7.07 (m, 1H), 5.52 - 5.41 (m, 2H), 3.61 (t, 2H), 3.42 - 3.32 (m, 1H), 3.25 - 3.07 (m, 2H), 2.81-2.72 (m, 1H), 1.30 (s, 3H), 1.26 - 1.13 (m, 2H), 0.88 (td, 2H), 0.44 (dd, 1H), 0.25 (t, 1H), -0.04 (s, 9H).；LC/MSm/z (M+Na)⁺ = 514.7 (⁷⁹ Br)。 Preparation 69 : (4aS,5aR)-3-(5- bromine -7- fluorine -1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole

Use 5-bromo-3-fluorobenzene-1,2-diamine (358 mg, 1.75 mmol) and Na₂ S₂ O₅ (380 mg, 2.00 mmol) A solution of Preparation 9 (510 mg, 1.66 mmol) in DMF (20.8 mL) was treated at room temperature. The vial was sealed and heated in a microwave reactor at 150°C for 2 h. The mixture was poured into 3% aqueous LiCl (40 mL) and the mixture was extracted with EtOAc (2×40 mL). Dry (Na₂ SO₄ ) Organic extract, filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-25%) to obtainTitle compound (815 g, 98%).¹ H NMR (400 MHz, CD₃ OD) δ 7.50 (s, 1H), 7.23-7.07 (m, 1H), 5.52-5.41 (m, 2H), 3.61 (t, 2H), 3.42-3.32 (m, 1H), 3.25-3.07 (m, 2H), 2.81-2.72 (m, 1H), 1.30 (s, 3H), 1.26-1.13 (m, 2H), 0.88 (td, 2H), 0.44 (dd, 1H), 0.25 (t, 1H),- 0.04 (s, 9H).; LC/MSm/z (M+Na)⁺ = 514.7 (⁷⁹ Br).

使用Et₃ SiH (118 mg, 1.02 mmol)在10℃下處理製備物69 (100 mg, 0.20 mmol)於TFA (2mL)中之溶液。將混合物在10℃下攪拌3 h。濃縮混合物並使用Na₂ CO₃ 飽和水溶液處理殘餘物。使用EtOAc (3 × 15 mL)萃取混合物。乾燥(Na₂ SO₄ )有機萃取物，過濾並濃縮。藉由層析[製備型HPLC, H₂ O:MeCN (w/0.05% NH₄ OH)]純化粗產物以得到標題化合物 (27.1 mg, 37%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.53 (s, 1H), 7.16 (d, 1H), 3.36-3.31 (m, 1H), 3.13 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s, 3H), 1.20 - 1.09 (m, 1H), 0.41 (dd, 1H), 0.24 (t, 1H)；LC/MSm/z (M+H)⁺ = 363.0 (⁷⁹ Br)。 Preparation 70 : (4aS,5aR)-3-(5- bromine -7- fluorine -1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole

Use Et₃ A solution of Preparation 69 (100 mg, 0.20 mmol) in TFA (2 mL) was treated with SiH (118 mg, 1.02 mmol) at 10°C. The mixture was stirred at 10°C for 3 h. Concentrate the mixture and use Na₂ CO₃ The residue was treated with saturated aqueous solution. The mixture was extracted with EtOAc (3×15 mL). Dry (Na₂ SO₄ ) Organic extract, filtered and concentrated. By chromatography [preparative HPLC, H₂ O:MeCN (w/0.05% NH₄ OH)] Purify the crude product to obtainTitle compound (27.1 mg, 37%).¹ H NMR (400 MHz, CD₃ OD) δ 7.53 (s, 1H), 7.16 (d, 1H), 3.36-3.31 (m, 1H), 3.13 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s , 3H), 1.20-1.09 (m, 1H), 0.41 (dd, 1H), 0.24 (t, 1H); LC/MSm/z (M+H)⁺ = 363.0 (⁷⁹ Br).

使用NaH (149 mg, 3.73 mmol)在0℃下處理製備物70 (1.53 g, 3.11 mmol)於THF (39 mL)中之溶液。在攪拌30 min之後，添加SEM-Cl (570 mg, 3.42 mmol)並將在10℃下混合物攪拌2 h。使用NH₄ Cl飽和水溶液(30 mL)處理混合物。使用EtOAc (3 × 40 mL)萃取混合物且合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-15%)純化粗產物以得到標題化合物 之混合物(1.60 g, 83%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.69 (dd, 1H), 7.26 (ddd, 1H), 6.24 - 5.97 (m, 2H), 5.53 - 5.46 (m, 2H), 4.10 (q, 1H), 3.63 (dd, 2H), 3.53 - 3.36 (m, 2H), 3.28 - 3.17 (m, 2H), 3.16 - 3.03 (m, 1H), 2.78 (d, 1H), 1.31 (s, 3H), 1.24 (t, 1H), 1.15 (dt, 1H), 0.92 (td, 2H), 0.76 (dt, 2H), 0.48 - 0.39 (m, 1H), 0.24 (td, 1H), -0.01 (s, 9H), -0.18 (s, 9H)；LC/MSm/z (M+H)⁺ = 622.8 (⁷⁹ Br)。 Preparation 71a : (4aS,5aR)-3-(6- bromine -4- fluorine -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole Preparation 71b : (4aS,5aR)-3-(5- bromine -7- fluorine -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole

A solution of Preparation 70 (1.53 g, 3.11 mmol) in THF (39 mL) was treated with NaH (149 mg, 3.73 mmol) at 0°C. After stirring for 30 min, SEM-Cl (570 mg, 3.42 mmol) was added and the mixture was stirred at 10°C for 2 h. Use NH₄ The mixture was treated with saturated aqueous Cl (30 mL). The mixture was extracted with EtOAc (3 × 40 mL) and the organic extracts were combined, dried (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-15%) to obtainTitle compound The mixture (1.60 g, 83%).¹ H NMR (400 MHz, CD₃ OD) δ 7.69 (dd, 1H), 7.26 (ddd, 1H), 6.24-5.97 (m, 2H), 5.53-5.46 (m, 2H), 4.10 (q, 1H), 3.63 (dd, 2H), 3.53 -3.36 (m, 2H), 3.28-3.17 (m, 2H), 3.16-3.03 (m, 1H), 2.78 (d, 1H), 1.31 (s, 3H), 1.24 (t, 1H), 1.15 (dt , 1H), 0.92 (td, 2H), 0.76 (dt, 2H), 0.48-0.39 (m, 1H), 0.24 (td, 1H), -0.01 (s, 9H), -0.18 (s, 9H); LC/MSm/z (M+H)⁺ = 622.8 (⁷⁹ Br).

使用Pd₂ (dba)₃ (105 mg, 0.12 mmol)及tert -BuDavePhos (78 mg, 0.23 mmol)處理於第三戊基醇(11.5 mL)中之製備物71a及71b之混合物之一部分(712 mg, 1.15 mmol)、胺基甲酸第三丁基酯(161 mg, 1.37 mmol)、Cs₂ CO₃ (746 mg, 2.29 mmol)。將反應液在100℃下加熱23 h。濃縮混合物並藉由層析(二氧化矽，EtOAc/PE = 0- 20%)純化粗製材料以得到標題化合物 之混合物(706 mg, 93%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.72 (s, 1H), 7.40 - 7.21 (m, 1H), 7.07 (d, 1H), 6.08 - 5.89 (m, 2H), 5.48 (d, 2H), δ 3.69 - 3.57 (m, 2H), 3.46 (dd, 1H), 3.25 - 3.02 (m, 3H), 2.78 (d, 1H), 2.50 (d, 1H), 1.55 (s, 9H), 1.43 (d, 1H), 1.33 - 1.23 (m, 5H), 1.20 - 1.09 (m, 2H), 0.99 - 0.83 (m, 5H), 0.82 - 0.69 (m, 1H), 0.42 (dd, 1H), 0.25 (t, 1H), -0.00 (s, 9H), -0.13 (s, 9H).；LC/MSm/z (M+H)⁺ = 658.0 Preparation 72a : (4- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base ) Tert-butyl carbamate Preparation 72b : (7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base ) Tert-butyl carbamate

Use Pd₂ (dba)₃ (105 mg, 0.12 mmol) andtert -BuDavePhos (78 mg, 0.23 mmol) treated with a part of the mixture of preparations 71a and 71b in tertiary amyl alcohol (11.5 mL) (712 mg, 1.15 mmol), tertiary butyl carbamate (161 mg , 1.37 mmol), Cs₂ CO₃ (746 mg, 2.29 mmol). The reaction solution was heated at 100°C for 23 h. The mixture was concentrated and the crude material was purified by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound The mixture (706 mg, 93%).¹ H NMR (400 MHz, CD₃ OD) δ 7.72 (s, 1H), 7.40-7.21 (m, 1H), 7.07 (d, 1H), 6.08-5.89 (m, 2H), 5.48 (d, 2H), δ 3.69-3.57 (m, 2H) ), 3.46 (dd, 1H), 3.25-3.02 (m, 3H), 2.78 (d, 1H), 2.50 (d, 1H), 1.55 (s, 9H), 1.43 (d, 1H), 1.33-1.23 ( m, 5H), 1.20-1.09 (m, 2H), 0.99-0.83 (m, 5H), 0.82-0.69 (m, 1H), 0.42 (dd, 1H), 0.25 (t, 1H), -0.00 (s , 9H), -0.13 (s, 9H).; LC/MSm/z (M+H)⁺ = 658.0

使用NaH (21.4 mg, 0.54 mmol)在0℃下處理於THF (5 mL)中之製備物72a及72b之混合物之一部分(235 mg, 0.36 mmol)。將混合物在15℃下攪拌30 min並使用碘甲烷(61 mg, 0.43 mmol)處理。將混合物攪拌16 h並使用NH₄ Cl飽和水溶液(15 mL)處理。使用EtOAc (2 × 20 mL)萃取混合物。收集有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-30%)純化粗產物以得到標題化合物 之混合物(120 mg, 50%)¹ H NMR (400 MHz, CD₃ OD) δ 7.39 (d, 1H), 7.01 (dd, 1H), 6.16 - 5.95 (m, 2H), 5.50 (d, 2H), 3.68 - 3.56 (m, 2H), 3.46 (t, 2H), 3.27 - 3.05 (m, 4H), 2.79 (d, 1H), 1.46 (s, 9H), 1.31 (s, 3H), 1.18 - 1.13 (m, 1H), 0.97 - 0.85 (m, 2H), 0.82 - 0.71 (m, 2H), 0.43 (dd, 1H), 0.26 (t, 1H), -0.00 (s, 9H), -0.14 (s, 9H)；LC/MSm/z (M+Na)⁺ = 694.0。 Preparation 73a : (4- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )( methyl ) Tert-butyl carbamate Preparation 73b : (7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )( methyl ) Tert-butyl carbamate

A portion (235 mg, 0.36 mmol) of the mixture of preparations 72a and 72b in THF (5 mL) was treated with NaH (21.4 mg, 0.54 mmol) at 0°C. The mixture was stirred at 15°C for 30 min and treated with methyl iodide (61 mg, 0.43 mmol). Stir the mixture for 16 h and use NH₄ Treatment with saturated aqueous Cl (15 mL). The mixture was extracted with EtOAc (2×20 mL). Collect organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 0-30%) to obtainTitle compound Mixture (120 mg, 50%)¹ H NMR (400 MHz, CD₃ OD) δ 7.39 (d, 1H), 7.01 (dd, 1H), 6.16-5.95 (m, 2H), 5.50 (d, 2H), 3.68-3.56 (m, 2H), 3.46 (t, 2H), 3.27 -3.05 (m, 4H), 2.79 (d, 1H), 1.46 (s, 9H), 1.31 (s, 3H), 1.18-1.13 (m, 1H), 0.97-0.85 (m, 2H), 0.82-0.71 (m, 2H), 0.43 (dd, 1H), 0.26 (t, 1H), -0.00 (s, 9H), -0.14 (s, 9H); LC/MSm/z (M+Na)⁺ = 694.0.

使用ZnBr₂ (201 mg, 0.89 mmol)在0℃下處理於DCM (2.0 mL)中之製備物73a及73b之混合物(120 mg, 0.178 mmol)。將混合物攪拌12 h，然後使用NaHCO₃ 飽和水溶液(10 mL)處理並使用DCM (2 × 20 mL)萃取混合物。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 之混合物(111 mg, 109%)¹ H NMR (400 MHz, CD₃ OD) δ 6.51 (d, 1H), 6.43 (dd, 1H), 5.97 (d, 1H), 5.86 (d, 1H), 5.47 (s, 2H), 3.62 (t, 2H), 3.41 (t, 2H), 3.25 - 3.03 (m, 3H), 2.84 (s, 3H), 2.82-2.75 (m, 1H), 1.30 (s, 3H), 1.17-1.10 (m, 1H), 0.92 (dd, 2H), 0.77 (t, 2H), 0.41 (dd, 1H), 0.25 (t, 1H), -0.00 (s, 9H), -0.13 (s, 9H)；LC/MSm/z (M+Na)⁺ = 594.0。 Preparation 74a : 4- fluorine -N- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- amine Preparation 74b : 7- fluorine -N- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- amine

Use ZnBr₂ (201 mg, 0.89 mmol) A mixture of preparations 73a and 73b (120 mg, 0.178 mmol) in DCM (2.0 mL) was treated at 0°C. Stir the mixture for 12 h, then use NaHCO₃ Saturated aqueous solution (10 mL) was treated and the mixture was extracted with DCM (2×20 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated to getTitle compound Mixture (111 mg, 109%)¹ H NMR (400 MHz, CD₃ OD) δ 6.51 (d, 1H), 6.43 (dd, 1H), 5.97 (d, 1H), 5.86 (d, 1H), 5.47 (s, 2H), 3.62 (t, 2H), 3.41 (t, 2H) ), 3.25-3.03 (m, 3H), 2.84 (s, 3H), 2.82-2.75 (m, 1H), 1.30 (s, 3H), 1.17-1.10 (m, 1H), 0.92 (dd, 2H), 0.77 (t, 2H), 0.41 (dd, 1H), 0.25 (t, 1H), -0.00 (s, 9H), -0.13 (s, 9H); LC/MSm/z (M+Na)⁺ = 594.0.

使用NaH (1.27 g, 31.9 mmol)在0℃下處理於THF (160 mL)中之製備物72a及72b之混合物(10.5 g, 16.0 mmol)。將混合物攪拌30 min並使用碘乙烷(3.30 g, 21 mmol)處理，且將混合物攪拌16 h。使用NH₄ Cl飽和水溶液(150 mL)處理混合物。使用EtOAc (2 × 200 mL)萃取混合物併合併有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-10%)純化粗產物以得到標題化合物 之混合物(8.26 g, 75%)。LC/MSm/z (M+H)⁺ = 453.3。 Preparation 75a : Ethyl (4- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base ) Tert-butyl carbamate Preparation 75b : Ethyl (7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base ) Tert-butyl carbamate

A mixture of preparations 72a and 72b (10.5 g, 16.0 mmol) in THF (160 mL) was treated with NaH (1.27 g, 31.9 mmol) at 0°C. The mixture was stirred for 30 min and treated with iodoethane (3.30 g, 21 mmol), and the mixture was stirred for 16 h. Use NH₄ The mixture was treated with saturated aqueous Cl (150 mL). The mixture was extracted with EtOAc (2 × 200 mL) and the organic layers were combined and dried (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-10%) to obtainTitle compound The mixture (8.26 g, 75%). LC/MSm/z (M+H)⁺ = 453.3.

使用ZnBr₂ (17.1 g, 75.7 mmol)在0℃下處理於DCM (151 mL)中之製備物75a及75b之混合物(10.39 g, 15.14 mmol)。將反應液升溫至30℃並攪拌16 h。將混合物傾倒至飽和NaHCO₃ (150 mL)中並過濾。使用DCM (2 × 100 mL)萃取濾液。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-10%)純化粗產物得到以得到標題化合物 之混合物(6.14 g, 69.2%)。LC/MSm/z (M+H) = 586.2。 Preparation 76a : N- Ethyl -4- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- amine Preparation 76b : N- Ethyl -7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- amine

Use ZnBr₂ (17.1 g, 75.7 mmol) A mixture of preparations 75a and 75b (10.39 g, 15.14 mmol) in DCM (151 mL) was treated at 0°C. The reaction solution was heated to 30°C and stirred for 16 h. Pour the mixture to saturated NaHCO₃ (150 mL) and filter. The filtrate was extracted with DCM (2×100 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-10%) to obtainTitle compound The mixture (6.14 g, 69.2%). LC/MSm/z (M+H) = 586.2.

使用4-溴-5-氟苯-1,2-二胺(328 mg, 1.60 mmol)及Na₂ S₂ O₅ (380 mg, 2.00 mmol)在室溫下處理製備物9 (467 mg, 1.52 mmol)於DMF (19 mL)中之溶液。密封小瓶並在150℃下於微波反應器中加熱2 h。將混合物傾倒至3% LiCl水溶液(80 mL)中並使用EtOAc (2 × 60 mL)萃取。合併有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0- 25%)純化粗產物以得到標題化合物 (644 mg, 86%)。¹ H NMR (400 MHz, CDCl₃ ) δ 9.96 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 5.46 - 5.28 (m, 2H), 3.58 - 3.49 (m, 2H), 3.20 - 3.07 (m, 3H), 2.74 (d, 1H), 1.29 (s, 3H), 1.21 - 1.10 (m, 1H), 0.95 - 0.83 (m, 2H), 0.43 (dd, 1H), 0.27 (t, 1H), -0.02 (s, 9H)。 Preparation 77 : (4aS,5aR)-3-(5- bromo -6- fluoro - 1H - benzo [d] imidazol -2- yl )-5a -methyl- 1-((2-( trimethyl (Silyl ) ethoxy ) methyl )-1,4,4a,5,5a,6 -hexahydrocycloprop (f) indazole

Use 4-bromo-5-fluorobenzene-1,2-diamine (328 mg, 1.60 mmol) and Na ₂ S ₂ O ₅ (380 mg, 2.00 mmol) to treat preparation 9 (467 mg, 1.52 mmol) at room temperature mmol) in DMF (19 mL). The vial was sealed and heated in a microwave reactor at 150°C for 2 h. The mixture was poured into 3% aqueous LiCl (80 mL) and extracted with EtOAc (2×60 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered, and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE=0-25%) to obtain the title compound (644 mg, 86%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.96 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 5.46-5.28 (m, 2H), 3.58-3.49 (m, 2H), 3.20-3.07 (m, 3H), 2.74 (d, 1H), 1.29 (s, 3H), 1.21-1.10 (m, 1H), 0.95-0.83 (m, 2H), 0.43 (dd, 1H), 0.27 ( t, 1H), -0.02 (s, 9H).

使用Pd₂ (dba)₃ (59 mg, 0.64 mmol)及(88 mg, 0.26 mmol)處理製備物77 (800 mg, 1.29 mmol)、胺基甲酸第三丁基酯(181 mg, 1.54 mmol)及Cs₂ CO₃ (838 mg, 2.57 mmol)於第三戊基醇(12.9 mL)中之混合物。將混合物加熱至100℃並保持16 h。添加額外Pd₂ (dba)₃ (59 mg, 0.64 mmol)及(88 mg, 0.26 mmol)並在100℃下繼續加熱16 h。濃縮混合物並藉由層析(二氧化矽，EtOAc/PE = 0- 20%)純化殘餘物以得到標題化合物 之混合物(480 mg, 57%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.34 (d, 1H), 7.49 (t, 1H), 6.82 (s, 1H), 6.15 - 5.97 (m, 2H), 5.47 - 5.34 (m, 2H), 3.62 - 3.37 (m, 5H), 3.10 (t, 2H), 2.73 (d, 1H), 1.55 (s, 9H), 1.28 (s, 3H), 1.12 (s, 1H), 0.99 - 0.77 (m, 4H), 0.39 (dd, 1H), 0.26 (q, 1H), -0.02 (s, 9H), -0.13 (d, 9H)；LC/MSm/z (M+H)⁺ = 658.3 Preparation 78a : (6- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base ) Tert-butyl carbamate Preparation 78b : (5- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base ) Tert-butyl carbamate

Use Pd₂ (dba)₃ (59 mg, 0.64 mmol) and (88 mg, 0.26 mmol) treatment preparation 77 (800 mg, 1.29 mmol), t-butyl carbamate (181 mg, 1.54 mmol) and Cs₂ CO₃ (838 mg, 2.57 mmol) in tertiary amyl alcohol (12.9 mL). The mixture was heated to 100°C and kept for 16 h. Add additional Pd₂ (dba)₃ (59 mg, 0.64 mmol) and (88 mg, 0.26 mmol) and continue heating at 100℃ for 16 h. The mixture was concentrated and the residue was purified by chromatography (silica dioxide, EtOAc/PE=0-20%) to obtainTitle compound The mixture (480 mg, 57%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.34 (d, 1H), 7.49 (t, 1H), 6.82 (s, 1H), 6.15-5.97 (m, 2H), 5.47-5.34 (m, 2H), 3.62-3.37 (m, 5H), 3.10 (t, 2H), 2.73 (d, 1H), 1.55 (s, 9H), 1.28 (s, 3H), 1.12 (s, 1H), 0.99-0.77 (m, 4H), 0.39 (dd, 1H) , 0.26 (q, 1H), -0.02 (s, 9H), -0.13 (d, 9H); LC/MSm/z (M+H)⁺ = 658.3

使用NaH (21.0 mg, 0.52 mmol)在0℃下處理於THF (4.6 mL)中之製備物78a及78b之混合物之一部分(230 mg, 0.35 mmol)。將混合物在15℃下攪拌20 min且然後使用碘甲烷(124 mg, 0.87 mmol)處理。在攪拌16 h之後，使用NH₄ Cl飽和水溶液(2 mL)稀釋混合物並使用EtOAc (2 × 10 mL)萃取。收集有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-30%)純化粗製材料以得到標題化合物 之混合物(286 mg, 100%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.63 (s, 0.5H), 7.51 (d, 0.5H), 7.40 (s, 1H), 6.10 (d, 2H), 5.50 - 5.37 (m, 2H), 3.64 - 3.53 (m, 2H), 3.56 - 3.43 (m, 3H), 3.28 (d, 3H), 3.20 - 3.07 (m, 2H), 2.76 (d, 1H), 1.38 (s, 7H), 1.30 (d, 5H), 1.15 (dt, 1H), 0.98 - 0.81 (m, 4H), 0.42 (dd, 1H), 0.29 (t, 1H), 0.01 (s, 9H), -0.09 (d, 9H)；LC/MSm/z (M+H)⁺ = 672.5 Preparation 79a : (6- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )( methyl ) Tert-butyl carbamate Preparation 79b : (5- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )( methyl ) Tert-butyl carbamate

A portion (230 mg, 0.35 mmol) of the mixture of preparations 78a and 78b in THF (4.6 mL) was treated with NaH (21.0 mg, 0.52 mmol) at 0°C. The mixture was stirred at 15°C for 20 min and then treated with methyl iodide (124 mg, 0.87 mmol). After stirring for 16 h, use NH₄ The mixture was diluted with saturated aqueous Cl (2 mL) and extracted with EtOAc (2×10 mL). Collect organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-30%) to obtainTitle compound The mixture (286 mg, 100%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.63 (s, 0.5H), 7.51 (d, 0.5H), 7.40 (s, 1H), 6.10 (d, 2H), 5.50-5.37 (m, 2H), 3.64-3.53 (m, 2H), 3.56-3.43 (m, 3H), 3.28 (d, 3H), 3.20-3.07 (m, 2H), 2.76 (d, 1H), 1.38 (s, 7H), 1.30 (d, 5H), 1.15 (dt, 1H), 0.98-0.81 (m, 4H), 0.42 (dd, 1H), 0.29 (t, 1H), 0.01 (s, 9H), -0.09 (d, 9H); LC/MSm/z (M+H)⁺ = 672.5

使用ZnBr₂ (479 mg, 2.13 mmol)在0℃下處理於DCM (4.26 mL)中之製備物79a及79b之混合物(286 mg, 0.425 mmol)。在15℃下攪拌12 h之後，將混合物傾倒至NaHCO₃ 飽和水溶液(20 mL)中且使用DCM (2 × 20 mL)萃取所得混合物。收集有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-40%)純化粗製材料以得到標題化合物 之混合物(160 mg, 66%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.41 (d, 0.57H), 7.21 (d, 0.43H), 7.07 (d, 0.43H), 6.73 (d, 0.57H), 6.06 (d, 1H), 6.07 - 5.95 (m, 1H), 5.46 - 5.34 (m, 2H), 4.05 (s, 1H), 3.61 - 3.37 (m, 5H), 3.09 (t, 2H), 2.94 (d, 3H), 2.73 (d, 1H), 1.30 - 1.22 (m, 3H), 1.11 (d, 1H), 0.91 (t, 2H), 0.85 - 0.80 (m, 2H), 0.38 (dd, 1H), 0.26 (t, 1H), -0.02 (d, 9H), -0.12 (s, 9H)；¹⁹ F NMR (376 MHz, CD₃ OD) δ -131.20.；LC/MSm/z (M+H)⁺ = 572 Preparation 80a : 5- fluorine -N- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- amine Preparation 80b : 6- fluorine -N- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- amine

Use ZnBr₂ (479 mg, 2.13 mmol) A mixture of preparations 79a and 79b (286 mg, 0.425 mmol) in DCM (4.26 mL) was treated at 0°C. After stirring for 12 h at 15°C, the mixture was poured into NaHCO₃ Saturated aqueous solution (20 mL) and extracted the resulting mixture with DCM (2×20 mL). Collect organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-40%) to obtainTitle compound The mixture (160 mg, 66%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.41 (d, 0.57H), 7.21 (d, 0.43H), 7.07 (d, 0.43H), 6.73 (d, 0.57H), 6.06 (d, 1H), 6.07-5.95 (m, 1H), 5.46-5.34 (m, 2H), 4.05 (s, 1H), 3.61-3.37 (m, 5H), 3.09 (t, 2H), 2.94 (d, 3H), 2.73 (d, 1H), 1.30-1.22 ( m, 3H), 1.11 (d, 1H), 0.91 (t, 2H), 0.85-0.80 (m, 2H), 0.38 (dd, 1H), 0.26 (t, 1H), -0.02 (d, 9H), -0.12 (s, 9H);¹⁹ F NMR (376 MHz, CD₃ OD) δ -131.20.; LC/MSm/z (M+H)⁺ = 572

使用固體KNO₃ (1140 mg, 11.3 mmol)逐份處理4-氟-2-甲氧基苯胺(1590 mg, 11.27 mmol)於濃H₂ SO₄ (9.55 mL)中之溶液，同時保持內部溫度低於5℃。將所得混合物在0℃下攪拌2 h且將混合物傾倒至冰水(100 mL)中，使用固體Na₂ CO₃ 緩慢中和並使用EtOAc (2 × 60 mL)萃取。乾燥(Na₂ SO₄ )有機層，過濾並濃縮以得到標題化合物 (2 g, 95%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.42 (d, 1H), 6.66 (d, 1H), 3.96 (s, 3H), 1.60 (s, 2H)；LC/MSm/z (M+H)⁺ =186.8。 Preparation 81 : 4- fluorine -2- Methoxy -5- Nitroaniline

Use solid KNO₃ (1140 mg, 11.3 mmol) treated 4-fluoro-2-methoxyaniline (1590 mg, 11.27 mmol) in concentrated H₂ SO₄ (9.55 mL) while keeping the internal temperature below 5°C. The resulting mixture was stirred at 0°C for 2 h and the mixture was poured into ice water (100 mL), using solid Na₂ CO₃ Slowly neutralize and extract with EtOAc (2 x 60 mL). Dry (Na₂ SO₄ ) The organic layer is filtered and concentrated to obtainTitle compound (2 g, 95%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.42 (d, 1H), 6.66 (d, 1H), 3.96 (s, 3H), 1.60 (s, 2H); LC/MSm/z (M+H)⁺ =186.8.

使用EDCI (1.22 g, 6.34 mmol)處理製備物81 (590 mg, 3.17 mmol)及製備物19 (605 mg, 3.80 mmol)於吡啶(45.3 mL)中之溶液。將混合物在室溫下攪拌16 h且然後傾倒至水(30 mL)中。使用EtOAc (2 × 40 mL)萃取所得混合物。合併有機層，使用NH₄ Cl飽和水溶液及鹽水依序洗滌，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化粗產物以得到標題化合物 (586 mg, 77%)。¹ H NMR (400 MHz, CDCl₃ ) δ 9.94 (s, 1H), 9.19 (d, 1H), 6.75 (d, 1H), 4.02 (s, 3H), 3.86 - 3.72 (m, 4H), 3.26 (q, 1H), 2.70 - 2.53 (m, 4H), 1.34 (d, 3H)。¹⁹ F NMR (376 MHz, CDCl₃ ) δ -118.16。LC/MSm/z (M+H) = 328.1；SFC方法：Chiral Tech AD-3 150 mm × 4.6 mm × 3 µm, CO₂ /IPA (0.05%i Pr₂ NEt )，40%等梯度，2.5 mL/min，管柱溫度：40℃，RT=4.027 min (99.31%) Preparation 82 : (S)- N -(4- fluorine -2- Methoxy -5- Nitrophenyl )-2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 81 (590 mg, 3.17 mmol) and Preparation 19 (605 mg, 3.80 mmol) in pyridine (45.3 mL) was treated with EDCI (1.22 g, 6.34 mmol). The mixture was stirred at room temperature for 16 h and then poured into water (30 mL). The resulting mixture was extracted with EtOAc (2×40 mL). Combine the organic layers and use NH₄ Wash Cl saturated aqueous solution and brine sequentially, and dry (MgSO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-50%) to obtainTitle compound (586 mg, 77%).¹ H NMR (400 MHz, CDCl₃ ) δ 9.94 (s, 1H), 9.19 (d, 1H), 6.75 (d, 1H), 4.02 (s, 3H), 3.86-3.72 (m, 4H), 3.26 (q, 1H), 2.70-2.53 ( m, 4H), 1.34 (d, 3H).¹⁹ F NMR (376 MHz, CDCl₃ ) δ -118.16. LC/MSm/z (M+H) = 328.1; SFC method: Chiral Tech AD-3 150 mm × 4.6 mm × 3 µm, CO₂ /IPA (0.05%i Pr₂ NEt), 40% isocratic, 2.5 mL/min, column temperature: 40℃, RT=4.027 min (99.31%)

使用NaH (107 mg, 2.69 mmol)在0℃下處理製備物82 (586 mg, 1.79 mmol)於THF (25 mL)中之混合物。將混合物在20℃下攪拌30 min並使用碘甲烷(305 mg, 2.15 mmol)處理。在攪拌16 h之後，使用NH₄ Cl飽和水溶液(2 mL)稀釋混合物並使用EtOAc (2 × 20 mL)萃取。收集有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0- 100%)純化粗製材料以得到標題化合物 (423 mg, 69%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.30 (d, 0.5H), 7.98 (d, 0.5H), 6.86 (dd, 1H), 4.03 - 3.93 (m, 3H), 3.65 (t, 2H), 3.60 - 3.46 (m, 2H), 3.21 - 3.12 (m, 4H), 3.02 - 2.92 (m, 0.5H), 2.55 (dt, 1H), 2.48 - 2.37 (m, 0.5H), 2.24 (dp, 2H), 1.18 (d, 1H), 1.11 (d, 2H)；LC/MSm/z (M+H) = 429.1。 Preparation 83 : (S)- N -(4- fluorine -2- Methoxy -5- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A mixture of Preparation 82 (586 mg, 1.79 mmol) in THF (25 mL) was treated with NaH (107 mg, 2.69 mmol) at 0°C. The mixture was stirred at 20°C for 30 min and treated with methyl iodide (305 mg, 2.15 mmol). After stirring for 16 h, use NH₄ The mixture was diluted with saturated aqueous Cl (2 mL) and extracted with EtOAc (2×20 mL). Collect organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (423 mg, 69%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.30 (d, 0.5H), 7.98 (d, 0.5H), 6.86 (dd, 1H), 4.03-3.93 (m, 3H), 3.65 (t, 2H), 3.60-3.46 (m, 2H), 3.21-3.12 (m, 4H), 3.02-2.92 (m, 0.5H), 2.55 (dt, 1H), 2.48-2.37 (m, 0.5H), 2.24 (dp, 2H), 1.18 (d, 1H), 1.11 (d, 2H); LC/MSm/z (M+H) = 429.1.

使用10% Pd/C (100 mg)及MeOH (5 mL)處理製備物83 (400 mg, 0.934 mmol)於MeOH (10 mL)中之混合物。將混合物脫氣並使用氬及H₂ 再填充三次，且然後在H₂ (3 atm)及25℃下攪拌24 h。添加額外10% Pd/C (100 mg)且將混合物在H₂ (3 atm)及25℃下再攪拌24 h。過濾反應液並濃縮濾液。藉由層析(二氧化矽，MeOH/DCM = 0-10%)純化粗產物以得到標題化合物 (239 mg, 83%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.41 - 7.29 (m, 3H), 6.60 (s, 1H), 6.35 (d, 1H), 4.46 (d, 1H), 3.74 (d, 3H), 3.72 - 3.60 (m, 4H), 3.18 - 3.12 (m, 4H), 2.63 - 2.52 (m, 1H), 2.51 - 2.39 (m, 3H), 1.19 (d, 1H), 1.14 (d, 2H)；LC/MSm/z (M+H) = 309.2。 Preparation 84 : (S)- N -(4,5- Diamine group -2- Methoxyphenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A mixture of Preparation 83 (400 mg, 0.934 mmol) in MeOH (10 mL) was treated with 10% Pd/C (100 mg) and MeOH (5 mL). Degas the mixture and use argon and H₂ Fill it three more times, and then in H₂ (3 atm) and stirring at 25°C for 24 h. Add an additional 10% Pd/C (100 mg) and place the mixture in H₂ (3 atm) and stirring at 25°C for another 24 h. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by chromatography (silica dioxide, MeOH/DCM = 0-10%) to obtainTitle compound (239 mg, 83%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.41-7.29 (m, 3H), 6.60 (s, 1H), 6.35 (d, 1H), 4.46 (d, 1H), 3.74 (d, 3H), 3.72-3.60 (m, 4H), 3.18- 3.12 (m, 4H), 2.63-2.52 (m, 1H), 2.51-2.39 (m, 3H), 1.19 (d, 1H), 1.14 (d, 2H); LC/MSm/z (M+H) = 309.2.

使用9 (722 mg, 2.52 mmol)及Na₂ S₂ O₅ (479 mg, 2.52 mmol)在20℃下處理製備物40 (900 mg, 2.52 mmol)於DMF (30 mL)中之混合物。將混合物在110℃下加熱15 h並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗產物得到標題化合物 (703 mg, 43.4%)。LC/MSm/z (M+H)⁺ = 643.2/645.2 (⁷⁹ Br,⁸¹ Br)。製備物 86a ： (S)-N -(6- 溴 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺 Preparation 85 : (S)- N -(6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use 9 (722 mg, 2.52 mmol) and Na₂ S₂ O₅ (479 mg, 2.52 mmol) A mixture of Preparation 40 (900 mg, 2.52 mmol) in DMF (30 mL) was treated at 20°C. The mixture was heated at 110°C for 15 h and concentrated. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (703 mg, 43.4%). LC/MSm/z (M+H)⁺ = 643.2/645.2 (⁷⁹ Br,⁸¹ Br).Preparation 86a : (S)- N -(6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

使用NaH (48.5 mg, 1.21 mmol)在0℃下處理製備物85 (600 mg, 0.93 mmol)於THF (30 mL)中之溶液。在攪拌30 min之後，添加SEM-Cl (233 mg, 1.40 mmol)並將混合物在20℃下攪拌2 h。使用NH₄ Cl飽和水溶液(1 mL)處理混合物並使用3:1 EtOAc/H₂ O (200 mL)稀釋。收集有機層且使用EtOAc (150 mL)萃取水層。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗製材料以得到標題化合物 之混合物(705 mg, 98%)。LC/MSm/z (M+H)⁺ = 773.0/775.0 (⁷⁹ Br,⁸¹ Br)。 Preparation 86a : (S)- N -(6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 85 (600 mg, 0.93 mmol) in THF (30 mL) was treated with NaH (48.5 mg, 1.21 mmol) at 0°C. After stirring for 30 min, SEM-Cl (233 mg, 1.40 mmol) was added and the mixture was stirred at 20°C for 2 h. Use NH₄ The mixture was treated with saturated aqueous Cl (1 mL) and used 3:1 EtOAc/H₂ Dilute with O (200 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (150 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound The mixture (705 mg, 98%). LC/MSm/z (M+H)⁺ = 773.0/775.0 (⁷⁹ Br,⁸¹ Br).

使用Pd(PPh₃ )₄ (30.0 mg, 0.026 mmol)及Zn(CN)₂ (152 mg, 1.29 mmol)在20℃下處理於NMP (10 mL)中之製備物86a及86b之混合物之一部分(200 mg, 0.258 mmol)。將所得混合物在160℃下於微波反應器中加熱1.5 h。將混合物傾倒至EtOAc/H₂ O (50/10 mL)中並收集有機層。使用EtOAc (50 mL)萃取水層。合併有機萃取物，使用鹽水洗滌，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗製材料以得到標題化合物 之混合物(165 mg, 89%)。LC/MSm/z (M+H)⁺ = 720.3。 Preparation 87a : (S)- N -(6- Cyano -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide Preparation 87b : (S)- N -(6- Cyano -1- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use Pd(PPh₃ )₄ (30.0 mg, 0.026 mmol) and Zn(CN)₂ (152 mg, 1.29 mmol) treated a portion (200 mg, 0.258 mmol) of the mixture of preparations 86a and 86b in NMP (10 mL) at 20°C. The resulting mixture was heated in a microwave reactor at 160°C for 1.5 h. Pour the mixture into EtOAc/H₂ O (50/10 mL) and collect the organic layer. The aqueous layer was extracted with EtOAc (50 mL). Combine the organic extracts, wash with brine, and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound The mixture (165 mg, 89%). LC/MSm/z (M+H)⁺ = 720.3.

使用N -溴琥珀醯亞胺(12.3 g, 68.9 mmol)在15℃下處理2,3-二氟-6-硝基苯胺(10.0 g, 57.4 mmol)於DMF (230 mL)中之溶液。將混合物在90℃下加熱6 h，且然後冷卻至室溫並傾倒至冰水中。使用EtOAc (2 × 100 mL)萃取混合物併合併有機萃取物，使用鹽水洗滌並乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-20%)純化粗製材料以得到標題化合物 (13.5 g, 93%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.22 (dd, 1H), 6.24 (s, 2H)。 Preparation 88. 4- bromine -2,3- Difluoro -6- Nitroaniline

useN -Bromosuccinimide (12.3 g, 68.9 mmol) was treated with a solution of 2,3-difluoro-6-nitroaniline (10.0 g, 57.4 mmol) in DMF (230 mL) at 15°C. The mixture was heated at 90 °C for 6 h, and then cooled to room temperature and poured into ice water. The mixture was extracted with EtOAc (2 × 100 mL) and the organic extracts were combined, washed with brine and dried (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound (13.5 g, 93%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.22 (dd, 1H), 6.24 (s, 2H).

使用SnCl₂ (48.2 g, 213 mmol)在20℃下處理製備物88 (13.5 g, 53.4 mmol)於EtOH (296 mL)中之溶液。將混合物在70℃下加熱16 h且然後冷卻至室溫。使用H₂ O (200 mL)稀釋混合物並使用NaHCO₃ 飽和水溶液(200 mL)洗滌。過濾混合物並使用EtOAc (100 mL)沖洗所收集固體。濃縮濾液。藉由層析(二氧化矽，EtOAc/PE = 0-60%)純化殘餘物以得到標題化合物 (8.50 g, 71.4%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.63 (dd, 1H), 3.49 (s, 2H), 3.35 (s, 2H)；LC/MSm/z (M+H)⁺ = 223.1/225.0 (⁷⁹ Br,⁸¹ Br)。 Preparation 89 : 5- bromine -3,4- Difluorobenzene -1,2- Diamine

Use SnCl₂ (48.2 g, 213 mmol) A solution of Preparation 88 (13.5 g, 53.4 mmol) in EtOH (296 mL) was treated at 20°C. The mixture was heated at 70°C for 16 h and then cooled to room temperature. Use H₂ O (200 mL) Dilute the mixture and use NaHCO₃ Wash with saturated aqueous solution (200 mL). The mixture was filtered and the collected solids were rinsed with EtOAc (100 mL). The filtrate was concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-60%) to obtainTitle compound (8.50 g, 71.4%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.63 (dd, 1H), 3.49 (s, 2H), 3.35 (s, 2H); LC/MSm/z (M+H)⁺ = 223.1/225.0 (⁷⁹ Br,⁸¹ Br).

使用製備物9 (6.87 g, 22.4 mmol)、Na₂ S₂ O₅ (2.13 g, 11.2 mmol)及DMSO (4.38 g, 56.0 mmol)在室溫下處理製備物89 (5.0 g, 22.42 mmol)於DMF (112 ml)中之溶液。將反應混合物在110℃下加熱16 h。將混合物傾倒至3% LiCl水溶液(100 mL)中並使用EtOAc (2 × 80 mL)萃取。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-20%)純化粗製材料以得到標題化合物 (10.17 g, 89%)。LC/MSm/z (M+H) = 509.3/511.3 (⁷⁹ Br,⁸¹ Br)。 Preparation 90 : (4aS,5aR)-3-(5- bromine -6,7- Difluoro -1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole

Use preparation 9 (6.87 g, 22.4 mmol), Na₂ S₂ O₅ (2.13 g, 11.2 mmol) and DMSO (4.38 g, 56.0 mmol) at room temperature to treat a solution of Preparation 89 (5.0 g, 22.42 mmol) in DMF (112 ml). The reaction mixture was heated at 110°C for 16 h. The mixture was poured into 3% aqueous LiCl (100 mL) and extracted with EtOAc (2×80 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound (10.17 g, 89%). LC/MSm/z (M+H) = 509.3/511.3 (⁷⁹ Br,⁸¹ Br).

在0℃下，向製備物90 (10.95 g, 2.49 mmol)於THF (269 mL)中之溶液中添加NaH (1.29 g, 32.2 mmol)。在攪拌30 min之後，添加SEM-Cl (3.94 g, 23.6 mmol)並將混合物在室溫下攪拌3 h。將混合物傾倒至NH₄ Cl飽和水溶液(150 mL)中並使用EtOAc (2 x 100 mL)萃取。收集有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-20%)純化粗製材料以得到標題化合物 之混合物(12.49 g, 90.8%)。¹ H NMR (400 MHz，甲醇-d ₄ ) δ 7.74 (ddd, 1H), 6.26 - 5.99 (m, 2H), 5.49 (d, 2H), 3.63 (t, 2H), 3.45 (dt, 2H), 3.23 (dd, 2H), 3.08 (td, 1H), 2.78 (dd, 1H), 1.31 (s, 3H), 1.15 (dt, 1H), 0.91 (td, 2H), 0.77 (ddd, 2H), 0.43 (dd, 1H), 0.24 (q, 1H), -0.01 (d, 9H), -0.14 (s, 4H), -0.17 (s, 5H)。 Preparation 91a : (4aS,5aR)-3-(6- bromine -4,5- Difluoro -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole Preparation 91b : (4aS,5aR)-3-(5- bromine -6,7- Difluoro -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole

At 0°C, to a solution of Preparation 90 (10.95 g, 2.49 mmol) in THF (269 mL) was added NaH (1.29 g, 32.2 mmol). After stirring for 30 min, SEM-Cl (3.94 g, 23.6 mmol) was added and the mixture was stirred at room temperature for 3 h. Pour the mixture to NH₄ Cl in a saturated aqueous solution (150 mL) and extracted with EtOAc (2 x 100 mL). Collect organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound The mixture (12.49 g, 90.8%).¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.74 (ddd, 1H), 6.26-5.99 (m, 2H), 5.49 (d, 2H), 3.63 (t, 2H), 3.45 (dt, 2H), 3.23 (dd, 2H), 3.08 (td, 1H), 2.78 (dd, 1H), 1.31 (s, 3H), 1.15 (dt, 1H), 0.91 (td, 2H), 0.77 (ddd, 2H), 0.43 (dd, 1H), 0.24 (q, 1H) ), -0.01 (d, 9H), -0.14 (s, 4H), -0.17 (s, 5H).

使用胺基甲酸第三丁基酯(2.60 g, 22.2 mmol)、Cs₂ CO₃ (9.63 g, 29.5 mmol)、Pd₂ (dba)₃ (1.35 g, 1.48 mmol)及(1.01 g, 2.95 mmol)在室溫下處理於第三戊基醇(148 mL)中之製備物91a及91b之混合物之一部分(9.45 g, 14.7 mmol)。將混合物在100℃下加熱16 h。濃縮混合物並藉由層析(二氧化矽，EtOAc/PE = 0-16%)純化殘餘物以得到標題化合物 之混合物(4.24 g, 43%)。LC/MSm/z (M+H) = 676.3。 Preparation 92a : (4,5- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base ) Tert-butyl carbamate Preparation 92b : (6,7- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base ) Tert-butyl carbamate

Use t-butyl carbamate (2.60 g, 22.2 mmol), Cs₂ CO₃ (9.63 g, 29.5 mmol), Pd₂ (dba)₃ (1.35 g, 1.48 mmol) and (1.01 g, 2.95 mmol) were treated with a portion (9.45 g, 14.7 mmol) of the mixture of preparations 91a and 91b in tertiary amyl alcohol (148 mL) at room temperature. The mixture was heated at 100°C for 16 h. The mixture was concentrated and the residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-16%) to obtainTitle compound The mixture (4.24 g, 43%). LC/MSm/z (M+H) = 676.3.

使用ZnBr₂ (8.78 g, 39.0 mmol)在0℃下處理92a及92b (5.27 g, 7.79 mmol)於DCM (78.0 mL)中之混合物。將混合物在15℃下攪拌12 h並傾倒至NaHCO₃ 飽和水溶液(70mL)中。使用DCM (2 × 80 mL)萃取混合物併合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-25%，然後MeOH/EtOAc = 0-15%)純化粗製材料以得到標題化合物 之混合物(2.8 g, 62.4%)。LC/MSm/z (M+H)⁺ = 576.3。 Preparation 93a : 4,5- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- amine Preparation 93b : 6,7- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- amine

Use ZnBr₂ (8.78 g, 39.0 mmol) A mixture of 92a and 92b (5.27 g, 7.79 mmol) in DCM (78.0 mL) was treated at 0°C. The mixture was stirred at 15°C for 12 h and poured into NaHCO₃ Saturated aqueous solution (70 mL). The mixture was extracted with DCM (2 × 80 mL) and the organic extracts were combined and dried (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-25%, then MeOH/EtOAc = 0-15%) to obtainTitle compound The mixture (2.8 g, 62.4%). LC/MSm/z (M+H)⁺ = 576.3.

使用製備物19 (1.12 g, 7.05 mmol)及EDCI (1.86 g, 9.72 mmol)在0℃下處理於吡啶(69.5 mL)中之製備物93a及93b之混合物(2.80 g, 4.86 mmol)。將混合物在室溫下攪拌19h，使用H₂ O (100 mL)稀釋並使用EtOAc (2 × 100 mL)萃取。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-25%)純化粗製材料以得到標題化合物 之混合物(3.07 g, 88.1%)。LC/MSm/z (M+H) = 717.6。 Preparation 94a : (S)- N -(4,5- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )-2- N- 𠰌 Hydroxypropionamide Preparation 94b : (S)- N -(6,7- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

A mixture of Preparations 93a and 93b (2.80 g, 4.86 mmol) in pyridine (69.5 mL) was treated with Preparation 19 (1.12 g, 7.05 mmol) and EDCI (1.86 g, 9.72 mmol) at 0°C. The mixture was stirred at room temperature for 19h, using H₂ Dilute with O (100 mL) and extract with EtOAc (2 x 100 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-25%) to obtainTitle compound The mixture (3.07 g, 88.1%). LC/MSm/z (M+H) = 717.6.

使用NaH (257 mg, 6.42 mmol)在0℃下處理製備物94a及94b之混合物(3.07 g, 4.28 mmol)於THF (61 mL)中之溶液。在15℃下攪拌30 min之後，添加碘甲烷(729 mg, 5.14 mmol)並將混合物在室溫下攪拌3 h。使用NH₄ Cl飽和水溶液(80 mL)稀釋混合物並使用EtOAc (2 × 80 mL)萃取。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化粗製材料以得到標題化合物 之混合物(3.26 g, 100%)。LC/MSm/z (M+H) = 731.4。 Preparation 95a : (S)- N -(4,5- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide Preparation 95b : (S)- N -(6,7- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

A solution of a mixture of preparations 94a and 94b (3.07 g, 4.28 mmol) in THF (61 mL) was treated with NaH (257 mg, 6.42 mmol) at 0°C. After stirring at 15°C for 30 min, methyl iodide (729 mg, 5.14 mmol) was added and the mixture was stirred at room temperature for 3 h. Use NH₄ The mixture was diluted with saturated aqueous Cl (80 mL) and extracted with EtOAc (2×80 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-50%) to obtainTitle compound The mixture (3.26 g, 100%). LC/MSm/z (M+H) = 731.4.

使用NaH (4.60 mg, 0.12 mmol)在0℃下處理製備物94a及94b之混合物之一部分(55 mg, 0.08 mmol)於THF (1.10 mL)中之溶液。在室溫下攪拌30 min之後，添加碘乙烷(14 mg, 0.09 mmol)且將混合物攪拌22 h。使用NH₄ Cl飽和水溶液(10 mL)稀釋混合物並使用EtOAc (2 × 15 mL)萃取。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物之混合物。LC/MSm/z (M+H) = 745.1。 Preparation 96a : (S)- N -(4,5- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )- N- Ethyl -2- N- 𠰌 Hydroxypropionamide Preparation 96b : (S)- N -(6,7- Difluoro -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- Ethyl -2- N- 𠰌 Hydroxypropionamide

A solution of a portion (55 mg, 0.08 mmol) of the mixture of preparations 94a and 94b in THF (1.10 mL) was treated with NaH (4.60 mg, 0.12 mmol) at 0°C. After stirring for 30 min at room temperature, iodoethane (14 mg, 0.09 mmol) was added and the mixture was stirred for 22 h. Use NH₄ The mixture was diluted with saturated aqueous Cl (10 mL) and extracted with EtOAc (2×15 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated to obtain a mixture of title compounds. LC/MSm/z (M+H) = 745.1.

使用NaH (474 mg, 11.9 mmol)在0℃下處理製備物62 (4.74 g, 9.88 mmol)於THF (124 mL)中之溶液。將混合物在0℃下攪拌30 min且添加SEM-Cl (1.81 g, 10.9 mmol)。將混合物在0℃下攪拌1 h並升溫至10℃，且攪拌1.5 h。使用NH₄ Cl飽和水溶液(50 mL)處理混合物並使用EtOAc (3 × 50 mL)萃取。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-40%)純化粗製材料以得到標題化合物 (2.42 g, 40%)。LC/MSm/z (M+H)⁺ = 610.3。 Preparation 97 : N - methyl -N -(6- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -5- base ) Acetamide

A solution of Preparation 62 (4.74 g, 9.88 mmol) in THF (124 mL) was treated with NaH (474 mg, 11.9 mmol) at 0°C. The mixture was stirred at 0°C for 30 min and SEM-Cl (1.81 g, 10.9 mmol) was added. The mixture was stirred at 0°C for 1 h and warmed to 10°C, and stirred for 1.5 h. Use NH₄ The mixture was treated with saturated aqueous Cl (50 mL) and extracted with EtOAc (3×50 mL). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-40%) to obtainTitle compound (2.42 g, 40%). LC/MSm/z (M+H)⁺ = 610.3.

使用LDA溶液(0.76 mL, 2N於THF/庚烷中)在-10℃下處理製備物97 (848 mg, 1.39 mmol)於THF (22 mL)中之溶液。將混合物在-10℃下攪拌30 min且添加苯磺醯氯(577 mg, 3.27 mmol)。將混合物在-10℃下攪拌2 h且然後使用NH₄ Cl飽和水溶液(20 mL)處理，並使用EtOAc (3 × 30 mL)萃取。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-30%)純化粗製材料以得到標題化合物 (404 mg, 45%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.71 (s, 1H), 7.39 (s, 1H), 6.20 - 5.93 (m, 2H), 5.53 - 5.33 (m, 2H), 3.92 - 3.66 (m, 2H), 3.57 (t, 2H), 3.54 - 3.47 (m, 2H), 3.47 - 3.38 (m, 1H), 3.30 (s, 3H), 3.19 - 3.03 (m, 2H), 2.74 (d, 1H), 2.34 (d, 3H), 1.28 (d, 3H), 1.13 (dt, 1H), 0.91 (ddd, 2H), 0.86 - 0.72 (m, 2H), 0.46 - 0.33 (m, 1H), 0.26 (q, 1H), -0.02 (s, 9H), -0.12 (s, 9H)；LC/MSm/z (M+H)⁺ = 644.3。 Preparation 98 : 2- chlorine -N- methyl -N -(6- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -5- base ) Acetamide

A solution of preparation 97 (848 mg, 1.39 mmol) in THF (22 mL) was treated with LDA solution (0.76 mL, 2N in THF/heptane) at -10°C. The mixture was stirred at -10°C for 30 min and benzenesulfonyl chloride (577 mg, 3.27 mmol) was added. The mixture was stirred at -10°C for 2 h and then NH was used₄ Treated with saturated aqueous Cl (20 mL) and extracted with EtOAc (3×30 mL). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-30%) to obtainTitle compound (404 mg, 45%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.71 (s, 1H), 7.39 (s, 1H), 6.20-5.93 (m, 2H), 5.53-5.33 (m, 2H), 3.92-3.66 (m, 2H), 3.57 (t, 2H), 3.54-3.47 (m, 2H), 3.47-3.38 (m, 1H), 3.30 (s, 3H), 3.19-3.03 (m, 2H), 2.74 (d, 1H), 2.34 (d, 3H), 1.28 ( d, 3H), 1.13 (dt, 1H), 0.91 (ddd, 2H), 0.86-0.72 (m, 2H), 0.46-0.33 (m, 1H), 0.26 (q, 1H), -0.02 (s, 9H ), -0.12 (s, 9H); LC/MSm/z (M+H)⁺ = 644.3.

類似於製備物38自4-氯-3-硝基苯胺及製備物19開始來製備標題化合物 。LC/MSm/z (M+H)⁺ = 309.0。 Preparation 99 : (S)- N -(4- Amino -3- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Similar to preparation 38, it was prepared starting from 4-chloro-3-nitroaniline and preparation 19Title compound . LC/MSm/z (M+H)⁺ = 309.0.

使用溴(1.24 g, 7.78 mmol)在20℃下處理製備物99 (1.20 g, 3.89 mmol)於DMF (20 mL)中之溶液。將混合物在20℃下攪拌15 h。將混合物冷卻至0℃並使用Et₃ N (10 mL)處理。在減壓下濃縮混合物且藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化殘餘物以得到標題化合物 (610 mg, 41%)。LC/MSm/z (M+H)⁺ = 388.8 (⁸¹ Br)。 Preparation 100 : (S)- N -(4- Amino -3- bromine -5- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 99 (1.20 g, 3.89 mmol) in DMF (20 mL) was treated with bromine (1.24 g, 7.78 mmol) at 20°C. The mixture was stirred at 20°C for 15 h. Cool the mixture to 0°C and use Et₃ N (10 mL) treatment. The mixture was concentrated under reduced pressure and the residue was purified by chromatography (silica dioxide, EtOAc/PE=0-100%) to obtainTitle compound (610 mg, 41%). LC/MSm/z (M+H)⁺ = 388.8 (⁸¹ Br).

使用濃HCl (1 mL)及鐵粉(389 mg, 6.97 mmol)處理製備物100 (900 mg, 2.32 mmol)於EtOH (80 mL)中之溶液。將混合物在70℃下攪拌2 h。將混合物冷卻至0℃並藉由添加濃NH₄ OH (2 mL)來調節至pH 7。過濾混合物且濃縮濾液。將殘餘物溶解於DCM (60 mL)中，攪拌1 h，並過濾。濃縮濾液以得到標題化合物 (802 mg, 87%)。LC/MSm/z (M+H)⁺ = 356.9 (⁷⁹ Br)。 Preparation 101 (S)- N -(3,4- Diamine group -5- Bromophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of preparation 100 (900 mg, 2.32 mmol) in EtOH (80 mL) was treated with concentrated HCl (1 mL) and iron powder (389 mg, 6.97 mmol). The mixture was stirred at 70°C for 2 h. Cool the mixture to 0°C and add concentrated NH₄ OH (2 mL) to adjust to pH 7. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (60 mL), stirred for 1 h, and filtered. Concentrate the filtrate to obtainTitle compound (802 mg, 87%). LC/MSm/z (M+H)⁺ = 356.9 (⁷⁹ Br).

將製備物9 (601 mg, 1.96 mmol)於DMF (25 mL)中之混合物添加至101 (700 mg, 1.96 mmol)及Na₂ S₂ O₅ (373 mg, 1.96 mmol)中並將混合物在110℃下加熱15 h。濃縮混合物且藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化殘餘物以得到標題化合物 (730 mg, 56%)。¹ H NMR (400 MHz, CDCl₃ ) δ 9.94 (s, 1H), 7.59 (s, 1H), 7.35 (s, 1H), 5.53 - 5.24 (m, 2H), 3.66 (t, 4H), 3.61 - 3.48 (m, 3H), 3.31 (s, 3H), 3.25 - 3.06 (m, 3H), 2.75 (d, 1H), 2.56 (dt, 2H), 2.38 - 2.23 (m, 2H), 1.30 (s, 3H), 1.14 (t, 4H), 0.92 (ddd, 2H), 0.43 (dd, 1H), 0.26 (t, 1H), -0.01 (s, 9H)；LC/MSm/z (M+H)⁺ = 645.0 (⁸¹ Br)。 Preparation 102 : (S)- N -(7- bromine -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Prepare preparation 9 (601 mg, 1.96 mmol) in DMF (25 mL) was added to 101 (700 mg, 1.96 mmol) and Na₂ S₂ O₅ (373 mg, 1.96 mmol) and heat the mixture at 110°C for 15 h. The mixture was concentrated and the residue was purified by chromatography (silica dioxide, EtOAc/PE=0-100%) to obtainTitle compound (730 mg, 56%).¹ H NMR (400 MHz, CDCl₃ ) δ 9.94 (s, 1H), 7.59 (s, 1H), 7.35 (s, 1H), 5.53-5.24 (m, 2H), 3.66 (t, 4H), 3.61-3.48 (m, 3H), 3.31 ( s, 3H), 3.25-3.06 (m, 3H), 2.75 (d, 1H), 2.56 (dt, 2H), 2.38-2.23 (m, 2H), 1.30 (s, 3H), 1.14 (t, 4H) , 0.92 (ddd, 2H), 0.43 (dd, 1H), 0.26 (t, 1H), -0.01 (s, 9H); LC/MSm/z (M+H)⁺ = 645.0 (⁸¹ Br).

使用NaH (57 mg, 1.41 mmol)及SEM-Cl (272 mg, 1.63 mmol)在0℃下處理製備物102 (700 mg, 1.09 mmol)於THF (50 mL)中之溶液。將混合物升溫至室溫並攪拌2 h。將混合物冷卻至0℃並使用NH₄ Cl飽和水溶液(1 mL)處理。使用水(50 mL)稀釋混合物並使用EtOAc (2 × 150 mL)萃取。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗製材料以得到標題化合物 (770 mg, 92%)。LC/MSm/z (M+H)⁺ = 775.2 (⁸¹ Br)。 Preparation 103 : (S)- N -(4- bromine -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 102 (700 mg, 1.09 mmol) in THF (50 mL) was treated with NaH (57 mg, 1.41 mmol) and SEM-Cl (272 mg, 1.63 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 2 h. Cool the mixture to 0°C and use NH₄ Treatment with saturated aqueous Cl (1 mL). The mixture was diluted with water (50 mL) and extracted with EtOAc (2×150 mL). The combined organic layer was washed with brine and dried (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (770 mg, 92%). LC/MSm/z (M+H)⁺ = 775.2 (⁸¹ Br).

酸

使用KOAc (125 mg, 1.27 mmol)、雙(頻哪醇)二硼(323 mg, 1.27 mmol)及Pd(dppf)Cl₂ (31 mg, 0.0424 mmol)處理製備物103 (328 mg, 0.424 mmol)於1,4-二噁烷(20 mL)中之溶液。將混合物加熱至100℃並攪拌15 h。將混合物冷卻至室溫並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%，然後MeOH/EtOAc = 0-100%)純化殘餘物以得到標題化合物 (245 mg, 86%)。LC/MSm/z (M+H)⁺ = 739.2 (⁷⁹ Br)。 Preparation 104 : (2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-6-((S)- N- methyl -2- N- 𠰌 Hydroxypropanamido )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -4- base )

acid

Use KOAc (125 mg, 1.27 mmol), bis(pinacol) diboron (323 mg, 1.27 mmol) and Pd(dppf)Cl₂ (31 mg, 0.0424 mmol) A solution of Preparation 103 (328 mg, 0.424 mmol) in 1,4-dioxane (20 mL) was treated. The mixture was heated to 100°C and stirred for 15 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%, then MeOH/EtOAc = 0-100%) to obtainTitle compound (245 mg, 86%). LC/MSm/z (M+H)⁺ = 739.2 (⁷⁹ Br).

使用NaBO₃ ·4H₂ O (104 mg, 0.673 mmol)於水(10 mL)中之溶液在0℃下處理製備物104 (350 mg, 0.224 mmol)於THF (30 mL)中之溶液。將混合物在20℃下攪拌5 h。將混合物分配於水(10 mL)與EtOAc (50 mL)之間。分離有機層且使用EtOAc (20 mL)萃取水層。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 (300 mg, 94%)。LC/MSm/z (M+H)⁺ = 711.3 Preparation 105 : (S)- N -(4- Hydroxyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use NaBO₃ ·4H₂ A solution of O (104 mg, 0.673 mmol) in water (10 mL) was treated with a solution of Preparation 104 (350 mg, 0.224 mmol) in THF (30 mL) at 0°C. The mixture was stirred at 20°C for 5 h. The mixture was partitioned between water (10 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layer was washed with brine and dried (Na₂ SO₄ ), filtered and concentrated to getTitle compound (300 mg, 94%). LC/MSm/z (M+H)⁺ = 711.3

使用K₂ CO₃ (88 mg, 0.63 mmol)及碘甲烷(45 mg, 0.32 mmol)在0℃下處理製備物105 (150 mg, 0.211 mmol)於DMF (3 mL)中之溶液。將混合物在20℃下攪拌2 h。使用水(10 mL)稀釋混合物並使用EtOAc (2 × 50 mL)萃取。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 (153 mg, 100%)。LC/MSm/z (M+H)⁺ = 725.3 Preparation 106 : (S)- N -(4- Methoxy -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -6- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use K₂ CO₃ A solution of preparation 105 (150 mg, 0.211 mmol) in DMF (3 mL) was treated at 0°C with iodomethane (88 mg, 0.63 mmol) and methyl iodide (45 mg, 0.32 mmol). The mixture was stirred at 20°C for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine and dried (Na₂ SO₄ ), filtered and concentrated to getTitle compound (153 mg, 100%). LC/MSm/z (M+H)⁺ = 725.3

使用5-溴-3-(三氟甲基)苯-1,2-二胺(240 mg, 0.94 mmol)及Na₂ S₂ O₅ (179 mg, 0.94 mmol)處理製備物9 (288 mg, 0.94 mmol)於DMF (10 mL)中之溶液。將混合物在110℃下加熱15 h並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化殘餘物以得到標題化合物 (430 mg, 84%)。LC/MSm/z (M+H)⁺ = 543.1 (⁸¹ Br)。 Preparation 107 : (4a S ,5a R )-3-(5- bromine -7-( Trifluoromethyl )-1 H- Benzo [ d ] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole

Use 5-bromo-3-(trifluoromethyl)benzene-1,2-diamine (240 mg, 0.94 mmol) and Na₂ S₂ O₅ (179 mg, 0.94 mmol) A solution of Preparation 9 (288 mg, 0.94 mmol) in DMF (10 mL) was treated. The mixture was heated at 110°C for 15 h and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (430 mg, 84%). LC/MSm/z (M+H)⁺ = 543.1 (⁸¹ Br).

使用NaH (34 mg, 0.84 mmol)及SEM-Cl (162 mg, 0.97 mmol)在0℃下處理製備物107 (350 mg, 0.65 mmol)於THF (20 mL)中之溶液。將混合物升溫至室溫並攪拌2 h。將混合物冷卻至0℃並使用NH₄ Cl飽和水溶液(1 mL)處理。使用水(50 mL)稀釋混合物並使用EtOAc (2 × 150 mL)萃取。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗製材料以得到標題化合物 (430 mg, 99%)。LC/MSm/z (M+H)⁺ = 673.0 (⁸¹ Br)。 Preparation 108 : (4a S ,5a R )-3-(6- bromine -4-( Trifluoromethyl )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole

A solution of Preparation 107 (350 mg, 0.65 mmol) in THF (20 mL) was treated with NaH (34 mg, 0.84 mmol) and SEM-Cl (162 mg, 0.97 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 2 h. Cool the mixture to 0°C and use NH₄ Treatment with saturated aqueous Cl (1 mL). The mixture was diluted with water (50 mL) and extracted with EtOAc (2×150 mL). The combined organic layer was washed with brine and dried (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (430 mg, 99%). LC/MSm/z (M+H)⁺ = 673.0 (⁸¹ Br).

使用BOC₂ O (199 mg, 1.7 mmol)、Cs₂ CO₃ (369 mg, 1.13 mmol)、(77 mg, 0.23 mmol)及Pd₂ (dba)₃ (52 mg, 0.057 mmol)處理製備物108 (380 mg, 0.57 mmol)於1,4-二噁烷(10 mL) (於第三戊基醇(10 mL)中)中之溶液。將混合物在100℃下加熱15 h。將混合物冷卻至室溫並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化殘餘物以得到標題化合物 (223 mg, 56%)。LC/MSm/z (M+H)⁺ = 708.4 Preparation 109 : (2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-4-( Trifluoromethyl )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base ) Tert-butyl carbamate

Use BOC₂ O (199 mg, 1.7 mmol), Cs₂ CO₃ (369 mg, 1.13 mmol), (77 mg, 0.23 mmol) and Pd₂ (dba)₃ (52 mg, 0.057 mmol) A solution of Preparation 108 (380 mg, 0.57 mmol) in 1,4-dioxane (10 mL) (in tertiary amyl alcohol (10 mL)) was treated. The mixture was heated at 100°C for 15 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (223 mg, 56%). LC/MSm/z (M+H)⁺ = 708.4

使用ZnBr₂ (350 mg, 1.55 mmol)處理製備物109 (220 mg, 0.31 mmol)於DCM (20 mL)中之溶液。將混合物在室溫下攪拌15 h。過濾混合物且使用水(50 mL)稀釋濾液，並使用DCM (2 × 50 mL)萃取。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 (170 mg, 90%)。LC/MSm/z (M+H)⁺ = 608.2。 Preparation 110 : 2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-4-( Trifluoromethyl )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- amine

Use ZnBr₂ (350 mg, 1.55 mmol) A solution of Preparation 109 (220 mg, 0.31 mmol) in DCM (20 mL) was treated. The mixture was stirred at room temperature for 15 h. The mixture was filtered and the filtrate was diluted with water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with brine and dried (Na₂ SO₄ ), filtered and concentrated to getTitle compound (170 mg, 90%). LC/MSm/z (M+H)⁺ = 608.2.

使用EDCI (107 mg, 0.56 mmol)處理製備物110 (170 mg, 0.28 mmol)及19 (89 mg, 0.56 mmol)於吡啶(5 mL)中之溶液。將混合物在室溫下攪拌15 h。使用水(50 mL)稀釋混合物並使用EtOAc (2 × 50 mL)萃取。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗製材料以得到標題化合物 (125 m, (60%)。LC/MSm/z (M+H)⁺ = 749.4。 Preparation 111 : (S)- N -(2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-4-( Trifluoromethyl )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )-2- N- 𠰌 Hydroxypropionamide

A solution of preparations 110 (170 mg, 0.28 mmol) and 19 (89 mg, 0.56 mmol) in pyridine (5 mL) was treated with EDCI (107 mg, 0.56 mmol). The mixture was stirred at room temperature for 15 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine and dried (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (125 m, (60%). LC/MSm/z (M+H)⁺ = 749.4.

使用NaH (10 mg, 0.25 mmol)在0℃下處理製備物111 (125 mg, 0.17 mmol)於THF (5 mL)中之溶液，隨後使用碘甲烷(36 mg, 0.25 mmol)處理。將混合物升溫至室溫並攪拌2 h。將混合物冷卻至0℃並使用NH₄ Cl飽和水溶液(0.3 mL)處理。使用水(50 mL)稀釋混合物並使用EtOAc (2 × 50 mL)萃取。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 (127 mg, 99%)。 Preparation 112 : (S)- N- methyl -N -(2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-4-( Trifluoromethyl )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )-2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 111 (125 mg, 0.17 mmol) in THF (5 mL) was treated with NaH (10 mg, 0.25 mmol) at 0°C, followed by treatment with methyl iodide (36 mg, 0.25 mmol). The mixture was warmed to room temperature and stirred for 2 h. Cool the mixture to 0°C and use NH₄ Treatment with saturated aqueous Cl (0.3 mL). The mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine and dried (Na₂ SO₄ ), filtered and concentrated to getTitle compound (127 mg, 99%).

將2,3-二胺基-5-溴苯甲酸甲酯(720 mg, 2.94 mmol)、9 (990 mg, 3.32 mmol)及NaHSO₃ (336 mg, 3.23 mmol)於EtOH (14.7 mL)及水(2.5 mL)中之混合物在90℃及空氣下加熱18 h。將混合物冷卻至室溫並使用水稀釋。使用DCM (× 3)萃取混合物並乾燥(MgSO₄ )合併之有機層，過濾並濃縮。將殘餘物在庚烷:EtOAc (1:1, 10 mL)中攪拌18 h並藉由過濾收集所得固體以得到標題化合物 (842 mg, 54%)，該標題化合物 呈灰棕色固體形式。¹ H NMR (600 MHz, CDCl₃ ) δ 10.85 (s, 1H), 8.18 (s, 1H), 8.01 (d, 1H), 5.50 - 5.33 (m, 2H), 4.02 (s, 3H), 3.61 - 3.51 (m, 3H), 3.18 (dd, 1H), 3.13 (d, 1H), 2.74 (d, 1H), 1.29 (s, 3H), 1.17 (dt, 1H), 0.92 (td, 2H), 0.43 (dd, 1H), 0.27 (t, 1H), -0.02 (s, 9H)；LC/MSm/z (M+H)⁺ = 531.5。 Preparation 113 : 5- bromine -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -7- Methyl formate

Combine 2,3-diamino-5-bromobenzoic acid methyl ester (720 mg, 2.94 mmol), 9 (990 mg, 3.32 mmol) and NaHSO₃ A mixture of (336 mg, 3.23 mmol) in EtOH (14.7 mL) and water (2.5 mL) was heated at 90°C in air for 18 h. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with DCM (× 3) and dried (MgSO₄ ) The combined organic layers are filtered and concentrated. The residue was stirred for 18 h in heptane: EtOAc (1:1, 10 mL) and the resulting solid was collected by filtration to obtainTitle compound (842 mg, 54%), theTitle compound It is in the form of a gray-brown solid.¹ H NMR (600 MHz, CDCl₃ ) δ 10.85 (s, 1H), 8.18 (s, 1H), 8.01 (d, 1H), 5.50-5.33 (m, 2H), 4.02 (s, 3H), 3.61-3.51 (m, 3H), 3.18 ( dd, 1H), 3.13 (d, 1H), 2.74 (d, 1H), 1.29 (s, 3H), 1.17 (dt, 1H), 0.92 (td, 2H), 0.43 (dd, 1H), 0.27 (t , 1H), -0.02 (s, 9H); LC/MSm/z (M+H)⁺ = 531.5.

` 使用製備物113 (2.77 g, 5.22 mmol)於THF (24 mL)中之溶液在0℃下處理NaH (4147 mg, 10.4 mmol)於THF (6 mL)中之懸浮液。將混合物在0℃下攪拌30 min且然後添加SEM-Cl (1310 mg, 7.83 mmol)。將混合物升溫至室溫並攪拌18 h。將混合物冷卻至0℃並使用NH₄ Cl飽和水溶液(5 mL)處理。蒸發有機溶劑並使用DCM (× 4)萃取所得混合物。使用鹽水洗滌合併之有機層，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-60%)純化粗製材料以得到標題化合物 (2.88 g, 83%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.10 (d, 1H), 7.92 (d, 1H), 6.18 (d, 2H), 5.49 - 5.33 (m, 2H), 4.06 (s, 3H), 3.63 (d, 1H), 3.52 (dt, 4H), 3.21 - 3.08 (m, 2H), 2.74 (d, 1H), 1.29 (s, 3H), 1.15 (dt, 1H), 0.94 - 0.80 (m, 4H), 0.41 (dd, 1H), 0.29 (t, 1H), -0.02 (s, 9H), -0.12 (s, 9H)。 Preparation 114 : 6- bromine -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -4- Methyl formate

` A solution of Preparation 113 (2.77 g, 5.22 mmol) in THF (24 mL) was used to treat a suspension of NaH (4147 mg, 10.4 mmol) in THF (6 mL) at 0°C. The mixture was stirred at 0°C for 30 min and then SEM-Cl (1310 mg, 7.83 mmol) was added. The mixture was warmed to room temperature and stirred for 18 h. Cool the mixture to 0°C and use NH₄ Treatment with saturated aqueous Cl (5 mL). The organic solvent was evaporated and the resulting mixture was extracted with DCM (×4). The combined organic layer was washed with brine and dried (MgSO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-60%) to obtainTitle compound (2.88 g, 83%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.10 (d, 1H), 7.92 (d, 1H), 6.18 (d, 2H), 5.49-5.33 (m, 2H), 4.06 (s, 3H), 3.63 (d, 1H), 3.52 (dt, 4H), 3.21-3.08 (m, 2H), 2.74 (d, 1H), 1.29 (s, 3H), 1.15 (dt, 1H), 0.94-0.80 (m, 4H), 0.41 (dd, 1H), 0.29 (t, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

將製備物114 (420 mg, 0.635 mmol)於DMF (4.2 mL)中之溶液添加至含有MeNH₂ ·HCl (64 mg, 0.95 mmol)、CuI (10 mg, 0.051 mmol)、N -(2,6-二甲基苯基)-6-羥基吡啶醯胺(25 mg, 0.10 mmol)及K₃ PO₄ (404 mg, 1.9 mmol)之小瓶中。將混合物在110℃下加熱20 h。將混合物冷卻至室溫並使用EtOAc稀釋。使用水(× 2)萃取混合物。使用鹽水洗滌有機層，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-70%)純化粗製材料以得到標題化合物 (231 mg, 60%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.37 (d, 1H), 6.92 (d, 1H), 6.13 (d, 2H), 5.46 - 5.35 (m, 2H), 4.06 (s, 3H), 3.64 - 3.43 (m, 5H), 3.22 - 3.07 (m, 2H), 2.94 (s, 3H), 2.73 (d, 1H), 1.65 (s, 1H), 1.28 (s, 3H), 1.13 (dt, 1H), 0.94 - 0.87 (m, 2H), 0.86 - 0.76 (m, 2H), 0.39 (dd, 1H), 0.30 (t, 1H), -0.02 (s, 9H), -0.13 (s, 9H)；LC/MSm/z (M+H)⁺ = 612.5。 Preparation 115 : 2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-6-( Methylamino )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -4- Methyl formate

The solution of preparation 114 (420 mg, 0.635 mmol) in DMF (4.2 mL) was added to the solution containing MeNH₂ ·HCl (64 mg, 0.95 mmol), CuI (10 mg, 0.051 mmol),N -(2,6-Dimethylphenyl)-6-hydroxypyridineamide (25 mg, 0.10 mmol) and K₃ PO₄ (404 mg, 1.9 mmol) in a vial. The mixture was heated at 110°C for 20 h. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was extracted with water (× 2). The organic layer was washed with brine and dried (MgSO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE=0-70%) to obtainTitle compound (231 mg, 60%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.37 (d, 1H), 6.92 (d, 1H), 6.13 (d, 2H), 5.46-5.35 (m, 2H), 4.06 (s, 3H), 3.64-3.43 (m, 5H), 3.22- 3.07 (m, 2H), 2.94 (s, 3H), 2.73 (d, 1H), 1.65 (s, 1H), 1.28 (s, 3H), 1.13 (dt, 1H), 0.94-0.87 (m, 2H) , 0.86-0.76 (m, 2H), 0.39 (dd, 1H), 0.30 (t, 1H), -0.02 (s, 9H), -0.13 (s, 9H); LC/MSm/z (M+H)⁺ = 612.5.

使用製備物115 (158 mg, 0.26 mmol)於THF (1.3 mL)中之溶液在0℃下逐滴處理LiAlH₄ (15 mg, 0.39 mmol)於四氫呋喃(0.39 mL)中之溶液。將混合物升溫至室溫並攪拌1 h。將混合物冷卻至0℃並使用羅謝爾氏鹽(Rochelle’s salt) (酒石酸鉀鈉)飽和水溶液處理。使用EtOAc (× 2)萃取混合物並使用鹽水洗滌合併之有機層，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 20-100%)純化粗製材料以得到標題化合物 (103 mg, 68%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.59 (d, 1H), 6.46 (d, 1H), 6.17 - 5.94 (m, 2H), 5.47 - 5.34 (m, 2H), 5.06 (s, 2H), 4.75 (s, 1H), 3.65 - 3.45 (m, 4H), 3.39 (d, 1H), 3.10 (dd, 2H), 2.89 (s, 3H), 2.76 - 2.65 (m, 1H), 1.27 (s, 3H), 1.10 (dt, 1H), 0.91 (ddd, 2H), 0.88 - 0.79 (m, 2H), 0.39 (dd, 1H), 0.25 (t, 1H), -0.02 (s, 9H), -0.11 (s, 9H)。 Preparation 116 : 2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-6-( Methylamino )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -4- base ) Methanol

A solution of preparation 115 (158 mg, 0.26 mmol) in THF (1.3 mL) was used to treat LiAlH dropwise at 0°C₄ (15 mg, 0.39 mmol) in tetrahydrofuran (0.39 mL). The mixture was warmed to room temperature and stirred for 1 h. The mixture was cooled to 0°C and treated with a saturated aqueous solution of Rochelle's salt (potassium sodium tartrate). The mixture was extracted with EtOAc (× 2) and the combined organic layer was washed with brine and dried (MgSO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane = 20-100%) to obtainTitle compound (103 mg, 68%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.59 (d, 1H), 6.46 (d, 1H), 6.17-5.94 (m, 2H), 5.47-5.34 (m, 2H), 5.06 (s, 2H), 4.75 (s, 1H), 3.65- 3.45 (m, 4H), 3.39 (d, 1H), 3.10 (dd, 2H), 2.89 (s, 3H), 2.76-2.65 (m, 1H), 1.27 (s, 3H), 1.10 (dt, 1H) , 0.91 (ddd, 2H), 0.88-0.79 (m, 2H), 0.39 (dd, 1H), 0.25 (t, 1H), -0.02 (s, 9H), -0.11 (s, 9H).

使用EDCI (84 mg, 0.44 mmol)處理製備物116 (102 mg, 0.18 mmol)及19 (42 mg, 0.262 mmol)於吡啶(1 mL)中之溶液。將混合物在室溫下攪拌18 h。濃縮混合物且將殘餘物分配於EtOAc與NaHCO₃ 飽和水溶液之間。分離有機層且使用EtOAc (× 2)萃取水層。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，[10:1 NH₄ OH/MeOH]/DCM = 0-16%)純化粗製材料以提供N -醯基產物及O -醯基產物之混合物。將混合物溶解於THF (1 mL)中並冷卻至0℃。添加NaH (18 mg, 0.45 mmol)且將混合物攪拌30 min，且然後使用碘甲烷(42 mg, 0.30 mmol)處理。將混合物升溫至室溫並攪拌16 h。將混合物冷卻至0℃並使用NH₄ Cl飽和水溶液處理。使用水稀釋混合物並使用EtOAc (× 3)萃取。乾燥(MgSO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 20-100%)純化粗製材料以得到標題化合物 (61 mg, (47%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.33 (s, 1H), 7.21 (s, 1H), 6.08 (d, 2H), 5.49 - 5.36 (m, 2H), 4.98 (d, 2H), 3.65 (t, 4H), 3.59 - 3.55 (m, 2H), 3.54 (s, 3H), 3.53 - 3.43 (m, 3H), 3.33 (s, 3H), 3.25 (q, 1H), 3.17 - 3.02 (m, 2H), 2.73 (d, 1H), 2.64 - 2.51 (m, 2H), 2.39 (dd, 2H), 1.29 (s, 3H), 1.15 (d, 3H), 1.14 - 1.08 (m, 1H), 0.90 (ddd, 2H), 0.85 - 0.76 (m, 2H), 0.41 (dd, 1H), 0.27 (t, 1H), -0.02 (s, 9H), -0.12 (s, 9H)。 Preparation 117 : (S)- N -(4-( Methoxymethyl )-2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 116 (102 mg, 0.18 mmol) and 19 (42 mg, 0.262 mmol) in pyridine (1 mL) was treated with EDCI (84 mg, 0.44 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was partitioned between EtOAc and NaHCO₃ Between saturated aqueous solutions. The organic layer was separated and the aqueous layer was extracted with EtOAc (×2). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. By chromatography (silica, [10:1 NH₄ OH/MeOH]/DCM = 0-16%) purify the crude material to provideN -Products andO -Mixtures of acyl products. The mixture was dissolved in THF (1 mL) and cooled to 0°C. NaH (18 mg, 0.45 mmol) was added and the mixture was stirred for 30 min, and then treated with methyl iodide (42 mg, 0.30 mmol). The mixture was warmed to room temperature and stirred for 16 h. Cool the mixture to 0°C and use NH₄ Treatment with saturated aqueous Cl solution. The mixture was diluted with water and extracted with EtOAc (×3). Dry (MgSO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane = 20-100%) to obtainTitle compound (61 mg, (47%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.33 (s, 1H), 7.21 (s, 1H), 6.08 (d, 2H), 5.49-5.36 (m, 2H), 4.98 (d, 2H), 3.65 (t, 4H), 3.59-3.55 ( m, 2H), 3.54 (s, 3H), 3.53-3.43 (m, 3H), 3.33 (s, 3H), 3.25 (q, 1H), 3.17-3.02 (m, 2H), 2.73 (d, 1H) , 2.64-2.51 (m, 2H), 2.39 (dd, 2H), 1.29 (s, 3H), 1.15 (d, 3H), 1.14-1.08 (m, 1H), 0.90 (ddd, 2H), 0.85-0.76 (m, 2H), 0.41 (dd, 1H), 0.27 (t, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

將1,2-二胺基-5-溴-3-氯苯(200 mg, 0.90 mmol)、NaHSO₃ (103 mg, 0.99 mmol)及製備物9 (304 mg, 0.99 mmol)於EtOH (3.7 mL)及水(0.8 mL)中之混合物在回流下加熱16 h。將混合物冷卻至室溫並使用水稀釋。在減壓下去除EtOH之後，使用EtOAc (× 3)萃取混合物。乾燥(MgSO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0-30%)純化粗製材料以得到標題化合物 (410 mg, 89%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.13 (s, 1H), 7.55 (d, 1H), 7.43 (d, 1H), 5.49 (d, 1H), 5.42 (d, 1H), 3.57 - 3.51 (m, 2H), 3.48 (d, 1H), 3.19 (d, 1H), 3.01 (dd, 1H), 2.73 (d, 1H), 1.27 (s, 3H), 1.16 (ddd, 1H), 0.84 (td, 2H), 0.41 (dd, 1H), 0.17 (dd, 1H), -0.06 (s, 9H)；LC/MSm/z (M+H)⁺ = 507.4 (⁷⁹ Br)。 Preparation 118 : (4a S ,5a R )-3-(5- bromine -7- chlorine -1 H- Benzo [ d ] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole

Combine 1,2-diamino-5-bromo-3-chlorobenzene (200 mg, 0.90 mmol), NaHSO₃ A mixture of (103 mg, 0.99 mmol) and Preparation 9 (304 mg, 0.99 mmol) in EtOH (3.7 mL) and water (0.8 mL) was heated under reflux for 16 h. The mixture was cooled to room temperature and diluted with water. After removing EtOH under reduced pressure, the mixture was extracted with EtOAc (×3). Dry (MgSO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane = 0-30%) to obtainTitle compound (410 mg, 89%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.13 (s, 1H), 7.55 (d, 1H), 7.43 (d, 1H), 5.49 (d, 1H), 5.42 (d, 1H), 3.57-3.51 (m, 2H), 3.48 (d, 1H), 3.19 (d, 1H), 3.01 (dd, 1H), 2.73 (d, 1H), 1.27 (s, 3H), 1.16 (ddd, 1H), 0.84 (td, 2H), 0.41 (dd, 1H) ), 0.17 (dd, 1H), -0.06 (s, 9H); LC/MSm/z (M+H)⁺ = 507.4 (⁷⁹ Br).

使用NaH (59 mg, 1.54 mmol)處理製備物118 (390 mg, 0.77 mmol)於THF (3.8 mL)中之溶液。將混合物在0℃下攪拌30 min且添加SEM-Cl (205 mg, 1.23 mmol)。將混合物在0℃下攪拌1.5 h。將混合物冷卻至0℃並使用NH₄ Cl飽和水溶液處理。蒸發THF。使用EtOAc (×4)萃取剩餘混合物。乾燥(MgSO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0-30%)純化粗製材料以得到標題化合物 之混合物(425 mg, 87%)。LC/MSm/z (M+H)⁺ = 637.6 (⁷⁹ Br)。 Preparation 119a : (4a S ,5a R )-3-(5- bromine -7- chlorine -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole Preparation 119b : (4a S ,5a R )-3-(6- bromine -4- chlorine -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole

A solution of Preparation 118 (390 mg, 0.77 mmol) in THF (3.8 mL) was treated with NaH (59 mg, 1.54 mmol). The mixture was stirred at 0°C for 30 min and SEM-Cl (205 mg, 1.23 mmol) was added. The mixture was stirred at 0°C for 1.5 h. Cool the mixture to 0°C and use NH₄ Treatment with saturated aqueous Cl solution. The THF was evaporated. The remaining mixture was extracted with EtOAc (×4). Dry (MgSO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane = 0-30%) to obtainTitle compound The mixture (425 mg, 87%). LC/MSm/z (M+H)⁺ = 637.6 (⁷⁹ Br).

將製備物119a及119b之混合物(542 mg, 0.85 mmol)於DMF (5.7 mL)中之溶液添加至MeNH₂ ·HCl (86 mg, 1.27 mmol)、CuI (13 mg, 0.068 mmol)、N -(2,6-二甲基苯基)-6-羥基吡啶醯胺(33 mg, 0.14 mmol)及K₃ PO₄ (541 mg, 2.6 mmol)中。將混合物在110℃下加熱18 h。使用EtOAc稀釋混合物並使用水(× 3)及鹽水洗滌。乾燥(MgSO₄ )有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0-30%)純化粗製材料以得到標題化合物 。(參考文獻：Bernhardson, D. J., Widlicka, D. W., Singer, R. A.,Org. Process Res. Dev. 2019 ,23 , 1538-1551) 製備物120：(121 mg, 24%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.66 (d, 1H), 6.58 (d, 1H), 6.03 (d, 2H), 5.44 - 5.34 (m, 2H), 3.59-3.44 (m, 5H), 3.11 (d, 2H), 3.07 (d, 1H), 2.89 (s, 3H), 2.71 (d, 1H), 1.28 (s, 3H), 1.11 (ddd, 1H), 0.95 - 0.87 (m, 2H), 0.86-0.77 (m, 2H), 0.38 (dd, 1H), 0.27 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H)。LC/MSm/z (M+H)⁺ = 588.6 製備物121：(162 mg, 33%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.91 (d, 1H), 6.65 (d, 1H), 6.28 (d, 1H), 6.25 (d, 1H), 5.44 (d, 1H), 5.39 (d, 1H), 3.68 (brs, 1H), 3.57 (dd, 2H), 3.41-3.27 (m, 3H), 3.13 (d, 1H), 3.06 (dd, 1H), 2.88 (s, 3H), 2.73 (d, 1H), 1.28 (s, 3H), 1.10 (ddd, 1H), 0.95 - 0.89 (m, 2H), 0.75 (td, 2H), 0.39 (dd, 1H), 0.27 (dd, 1H), -0.01 (s, 9H), -0.16 (s, 9H)。LC/MSm/z (M+H)⁺ = 588.6 Preparation 120 : 7- chlorine -N- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -5- amine Preparation 121 : 4- chlorine -N- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- amine

A solution of a mixture of preparations 119a and 119b (542 mg, 0.85 mmol) in DMF (5.7 mL) was added to MeNH₂ ·HCl (86 mg, 1.27 mmol), CuI (13 mg, 0.068 mmol),N -(2,6-Dimethylphenyl)-6-hydroxypyridineamide (33 mg, 0.14 mmol) and K₃ PO₄ (541 mg, 2.6 mmol). The mixture was heated at 110°C for 18 h. The mixture was diluted with EtOAc and washed with water (×3) and brine. Dry (MgSO₄ ) Organic layer, filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane = 0-30%) to obtainTitle compound . (Reference: Bernhardson, D. J., Widlicka, D. W., Singer, R. A.,Org. Process Res. Dev. 2019 ,twenty three , 1538-1551) Preparation 120: (121 mg, 24%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.66 (d, 1H), 6.58 (d, 1H), 6.03 (d, 2H), 5.44-5.34 (m, 2H), 3.59-3.44 (m, 5H), 3.11 (d, 2H), 3.07 ( d, 1H), 2.89 (s, 3H), 2.71 (d, 1H), 1.28 (s, 3H), 1.11 (ddd, 1H), 0.95-0.87 (m, 2H), 0.86-0.77 (m, 2H) , 0.38 (dd, 1H), 0.27 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H). LC/MSm/z (M+H)⁺ = 588.6 Preparation 121: (162 mg, 33%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.91 (d, 1H), 6.65 (d, 1H), 6.28 (d, 1H), 6.25 (d, 1H), 5.44 (d, 1H), 5.39 (d, 1H), 3.68 (brs, 1H) , 3.57 (dd, 2H), 3.41-3.27 (m, 3H), 3.13 (d, 1H), 3.06 (dd, 1H), 2.88 (s, 3H), 2.73 (d, 1H), 1.28 (s, 3H) ), 1.10 (ddd, 1H), 0.95-0.89 (m, 2H), 0.75 (td, 2H), 0.39 (dd, 1H), 0.27 (dd, 1H), -0.01 (s, 9H), -0.16 ( s, 9H). LC/MSm/z (M+H)⁺ = 588.6

將製備物19 (24.4 mg, 0.15 mmol)、120 (82 mg, 0.14 mmol)、吡啶(0.56 mL, 0.70 mmol)及T₃ P (50 wt%於EtOAc中，0.17 mL, 0.28 mmol)於EtOAc (0.9 mL)中之混合物在室溫下攪拌18 h。使用DMF (0.6 mL)處理混合物且將混合物在室溫下再攪拌24 h。使用EtOAc及水稀釋混合物。在分離各層之後，使用水(× 2)及鹽水洗滌有機層。乾燥(MgSO₄ )剩餘有機部分，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷，10-80%梯度)純化粗製材料以得到標題化合物 (42.8 mg, 42%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.55 (d, 1H), 7.21 (s, 1H), 6.38 (d, 2H), 5.45 (d, 1H), 5.41 (d, 1H), 3.65 (dd, 4H), 3.60-3.54 (m, 2H), 3.40 (d, 2H), 3.31 (s, 3H), 3.23 (q, 1H), 3.14 (d, 1H), 3.06 (dd, 1H), 2.74 (d, 1H), 2.57 (ddd, 2H), 2.32 (ddd, 2H), 1.77 (brs, 1H), 1.28 (s, 3H), 1.18-1.06 (m, 4H), 0.91 (ddd, 2H), 0.78 (td, 2H), 0.41 (dd, 1H), 0.26 (dd, 1H), -0.02 (s, 9H), -0.16 (s, 9H)；LC/MSm/z (M+H)⁺ = 729.7。 Preparation 122: (S) - N - (7- chloro -2 - ((4a S, 5a R) -5a- methyl-1 - ((2- (trimethyl silicon based) ethoxy) methyl )-1,4,4a,5,5a,6 -hexahydrocycloprop [ f ] indazol- 3 -yl )-1-((2-( trimethylsilyl ) ethoxy ) methyl )- 1 H - benzo [d] imidazol-5-yl) - N - methyl -2- N - propan-quinolyl 𠰌 Amides

The preparation 19 (24.4 mg, 0.15 mmol), 120 (82 mg, 0.14 mmol), pyridine (0.56 mL, 0.70 mmol) and T ₃ P (50 wt% in EtOAc, 0.17 mL, 0.28 mmol) in EtOAc ( The mixture in 0.9 mL) was stirred at room temperature for 18 h. The mixture was treated with DMF (0.6 mL) and the mixture was stirred at room temperature for another 24 h. The mixture was diluted with EtOAc and water. After separating the layers, the organic layer was washed with water (× 2) and brine. The remaining organic portion was dried (MgSO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica dioxide, EtOAc/heptane, 10-80% gradient) to obtain the title compound (42.8 mg, 42%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (d, 1H), 7.21 (s, 1H), 6.38 (d, 2H), 5.45 (d, 1H), 5.41 (d, 1H), 3.65 (dd, 4H), 3.60-3.54 (m, 2H), 3.40 (d, 2H), 3.31 (s, 3H), 3.23 (q, 1H), 3.14 (d, 1H), 3.06 (dd, 1H), 2.74 (d , 1H), 2.57 (ddd, 2H), 2.32 (ddd, 2H), 1.77 (brs, 1H), 1.28 (s, 3H), 1.18-1.06 (m, 4H), 0.91 (ddd, 2H), 0.78 ( td, 2H), 0.41 (dd, 1H), 0.26 (dd, 1H), -0.02 (s, 9H), -0.16 (s, 9H); LC/MS m/z (M+H) ⁺ = 729.7.

將製備物120 (785 mg, 1.33 mmol)於DCM中之溶液冷卻至0℃。使用Et₃ N (0.56 mL, 4.00 mmol)及乙醯氯(0.14 mL, 2.00 mmol)處理溶液。將混合物在0℃下攪拌20 min並使用NaHCO₃ 飽和水溶液處理。使用DCM (× 3)萃取水層，且乾燥(MgSO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0-50%)純化粗製材料以得到標題化合物 123 (807 mg, 64%)。LC/MSm/z (M+H)⁺ = 630.5。 Preparation 123 : N -(7- chlorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- Methyl acetamide

A solution of preparation 120 (785 mg, 1.33 mmol) in DCM was cooled to 0°C. Use Et₃ Treat the solution with N (0.56 mL, 4.00 mmol) and acetyl chloride (0.14 mL, 2.00 mmol). Stir the mixture at 0°C for 20 min and use NaHCO₃ Saturated aqueous solution treatment. The aqueous layer was extracted with DCM (× 3) and dried (MgSO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane=0-50%) to obtainTitle compound 123 (807 mg, 64%). LC/MSm/z (M+H)⁺ = 630.5.

向製備物123 (675 mg, 1.07 mmol)、2,4,6-三乙烯基環三硼氧烷吡啶複合物(297 mg, 1.24 mmol)、Pd(OAc)₂ (9.3 mg, 0.04 mmol)及SPhos (34 mg, 0.08 mmol)於1,4-二噁烷(5.4 mL)中之混合物中添加3 M K₃ PO₄ (0.82 mL, 2.47 mmol)。將混合物在100℃下加熱20 h。過濾混合物並使用EtOAc沖洗固體。使用水稀釋濾液並使用EtOAc (× 3)萃取。乾燥(MgSO₄ )合併之有機萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0-50%)純化粗製材料以得到標題化合物 (391 mg, 59%)。LC/MSm/z (M+H)⁺ = 622.5。 Preparation 124 : N- methyl -N -(2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-7- Vinyl -1 H- Benzo [d] Imidazole -5- base ) Acetamide.

To preparation 123 (675 mg, 1.07 mmol), 2,4,6-trivinylcycloboroxane pyridine complex (297 mg, 1.24 mmol), Pd(OAc)₂ Add 3 M K to the mixture of (9.3 mg, 0.04 mmol) and SPhos (34 mg, 0.08 mmol) in 1,4-dioxane (5.4 mL)₃ PO₄ (0.82 mL, 2.47 mmol). The mixture was heated at 100°C for 20 h. The mixture was filtered and the solids were rinsed with EtOAc. The filtrate was diluted with water and extracted with EtOAc (×3). Dry (MgSO₄ ) The combined organic extracts are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane=0-50%) to obtainTitle compound (391 mg, 59%). LC/MSm/z (M+H)⁺ = 622.5.

使用10% Pd/C (20 mg)處理製備物124 (87 mg, 0.14 mmol)於MeOH (2 mL)中之溶液。使用N₂ 將混合物脫氣並使用H₂ 回填三次。將混合物在室溫及H₂ (3 atm)下攪拌18 h。過濾混合物並濃縮濾液以得到標題化合物 (87 mg，定量)。¹ H NMR (600 MHz, CDCl₃ ) δ 7.45 (d, 1H), 6.91 (d, 1H), 6.14 (q, 2H), 5.54 - 5.37 (m, 2H), 3.56 (t, 2H), 3.38 - 3.32 (m, 2H), 3.30 (s, 3H), 3.18 - 3.10 (m, 3H), 3.07 (dd, 1H), 2.74 (d, 1H), 1.97 (s, 1H), 1.88 (s, 3H), 1.34 (t, 3H), 1.27 (s, 3H), 1.11 (dt, 1H), 0.91 (td, 2H), 0.79 - 0.64 (m, 2H), 0.39 (dd, 1H), 0.24 (t, 1H), -0.02 (s, 9H), -0.18 (s, 9H)。 Preparation 124a : N -(7- Ethyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -5- base )- N- Methyl acetamide

A solution of preparation 124 (87 mg, 0.14 mmol) in MeOH (2 mL) was treated with 10% Pd/C (20 mg). Use N₂ Degas the mixture and use H₂ Backfill three times. Put the mixture at room temperature and H₂ (3 atm) stirring for 18 h. Filter the mixture and concentrate the filtrate to obtainTitle compound (87 mg, quantitative).¹ H NMR (600 MHz, CDCl₃ ) δ 7.45 (d, 1H), 6.91 (d, 1H), 6.14 (q, 2H), 5.54-5.37 (m, 2H), 3.56 (t, 2H), 3.38-3.32 (m, 2H), 3.30 ( s, 3H), 3.18-3.10 (m, 3H), 3.07 (dd, 1H), 2.74 (d, 1H), 1.97 (s, 1H), 1.88 (s, 3H), 1.34 (t, 3H), 1.27 (s, 3H), 1.11 (dt, 1H), 0.91 (td, 2H), 0.79-0.64 (m, 2H), 0.39 (dd, 1H), 0.24 (t, 1H), -0.02 (s, 9H) , -0.18 (s, 9H).

使用KOH (155 mg, 2.76 mmol)處理製備物124 (86 mg, 0.14 mmol)於1:1 EtOH:水中之溶液。在90℃下加熱混合物並攪拌72 h。將混合物冷卻至室溫並使用水稀釋，使用DCM (× 3)萃取。乾燥(MgSO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0- 80%梯度)純化粗製材料以得到標題化合物 (37 mg, 46%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.88 (d, 1H), 6.51 (d, 1H), 6.13 - 5.90 (m, 2H), 5.50 - 5.29 (m, 2H), 3.57 (t, 2H), 3.33 (d, 1H), 3.25 (dd, 2H), 3.16 - 3.01 (m, 4H), 2.89 (s, 3H), 2.77 - 2.69 (m, 1H), 1.32 (t, 3H), 1.27 (s, 3H), 1.14 - 1.04 (m, 1H), 0.96 - 0.83 (m, 3H), 0.72 (td, 2H), 0.38 (dd, 1H), 0.26 (t, 1H), -0.01 (s, 9H), -0.16 (s, 9H)；LC/MSm/z (M+H)⁺ = 582.5。 Preparation 125 : 7- Ethyl -N- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -5- amine

A solution of Preparation 124 (86 mg, 0.14 mmol) in 1:1 EtOH:water was treated with KOH (155 mg, 2.76 mmol). The mixture was heated at 90°C and stirred for 72 h. The mixture was cooled to room temperature and diluted with water, extracted with DCM (×3). Dry (MgSO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane=0-80% gradient) to obtainTitle compound (37 mg, 46%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.88 (d, 1H), 6.51 (d, 1H), 6.13-5.90 (m, 2H), 5.50-5.29 (m, 2H), 3.57 (t, 2H), 3.33 (d, 1H), 3.25 ( dd, 2H), 3.16-3.01 (m, 4H), 2.89 (s, 3H), 2.77-2.69 (m, 1H), 1.32 (t, 3H), 1.27 (s, 3H), 1.14-1.04 (m, 1H), 0.96-0.83 (m, 3H), 0.72 (td, 2H), 0.38 (dd, 1H), 0.26 (t, 1H), -0.01 (s, 9H), -0.16 (s, 9H); LC /MSm/z (M+H)⁺ = 582.5.

使用EDCI (31 mg, 0.159 mmol)處理製備物125 (37 mg, 0.064 mmol)及製備物19 (15 mg, 0.095 mmol)於吡啶(1 mL)中之溶液。將混合物在室溫下攪拌18 h。濃縮混合物且使用水稀釋殘餘物。使用EtOAc (× 3)萃取有機層。乾燥(MgSO₄ )合併之有機層，過濾並濃縮以得到標題化合物 (45 mg, 98%)。¹ H NMR (600 MHz, CDCl₃ ) δ 7.47 (s, 1H), 6.92 (s, 1H), 6.14 (s, 2H), 5.55 - 5.34 (m, 2H), 3.65 (dt, 4H), 3.57 (td, 2H), 3.40 - 3.33 (m, 2H), 3.33 (s, 3H), 3.26 (q, 1H), 3.15 (q, 3H), 3.06 (dd, 1H), 2.75 (d, 1H), 2.59 - 2.52 (m, 2H), 2.40 (dt, 2H), 1.34 (t, 3H), 1.29 (s, 3H), 1.25 (d, 1H), 1.17 (d, 3H), 1.15 - 1.06 (m, 1H), 0.92 (ddd, 2H), 0.75 (td, 2H), 0.40 (dd, 1H), 0.26 (t, 1H), -0.01 (s, 9H), -0.16 (s, 9H) ；LC/MSm/z (M+H)⁺ = 723.7。 Preparation 126 : (S)- N -(7- Ethyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 125 (37 mg, 0.064 mmol) and Preparation 19 (15 mg, 0.095 mmol) in pyridine (1 mL) was treated with EDCI (31 mg, 0.159 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was diluted with water. The organic layer was extracted with EtOAc (×3). Dry (MgSO₄ ) Combine the organic layers, filter and concentrate to obtainTitle compound (45 mg, 98%).¹ H NMR (600 MHz, CDCl₃ ) δ 7.47 (s, 1H), 6.92 (s, 1H), 6.14 (s, 2H), 5.55-5.34 (m, 2H), 3.65 (dt, 4H), 3.57 (td, 2H), 3.40-3.33 ( m, 2H), 3.33 (s, 3H), 3.26 (q, 1H), 3.15 (q, 3H), 3.06 (dd, 1H), 2.75 (d, 1H), 2.59-2.52 (m, 2H), 2.40 (dt, 2H), 1.34 (t, 3H), 1.29 (s, 3H), 1.25 (d, 1H), 1.17 (d, 3H), 1.15-1.06 (m, 1H), 0.92 (ddd, 2H), 0.75 (td, 2H), 0.40 (dd, 1H), 0.26 (t, 1H), -0.01 (s, 9H), -0.16 (s, 9H); LC/MSm/z (M+H)⁺ = 723.7.

使用Et₃ N (0.35 mL, 2.52 mmol)、Boc₂ O (412 mg, 1.89 mmol)及DMAP (154 mg, 1.26 mmol)在室溫下處理製備物121 (740 mg, 1.26 mmol)於THF (6.3 mL)中之溶液。將混合物在室溫下攪拌18 h且添加額外之Et₃ N (0.35 mL, 2.52 mmol)、Boc₂ O (412 mg, 1.89 mmol)及DMAP (154 mg, 1.26 mmol)。將反應混合物加熱至60℃並再攪拌36 h。濃縮混合物並藉由層析(二氧化矽，EtOAc/庚烷= 0-50%)純化殘餘物以得到標題化合物 (637.3 mg, 74%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.33 (d, 1H), 7.20 (d, 1H), 6.08 (d, 2H), 5.43 (d, 1H), 5.39 (d, 1H), 3.59-3.46 (m, 5H), 3.30 (s, 3H), 3.20-3.07 (m, 2H), 2.73 (d, 1H), 1.44 (s, 9H), 1.28 (s, 3H), 1.17-1.08 (m, 1H), 0.95-0.88 (m, 2H), 0.86-0.78 (m, 2H), 0.40 (dd, 1H), 0.27 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H)。 Preparation 127 : (4- chlorine -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )( methyl ) Tert-butyl carbamate

Use Et₃ N (0.35 mL, 2.52 mmol), Boc₂ A solution of preparation 121 (740 mg, 1.26 mmol) in THF (6.3 mL) was treated with O (412 mg, 1.89 mmol) and DMAP (154 mg, 1.26 mmol) at room temperature. The mixture was stirred at room temperature for 18 h and additional Et was added₃ N (0.35 mL, 2.52 mmol), Boc₂ O (412 mg, 1.89 mmol) and DMAP (154 mg, 1.26 mmol). The reaction mixture was heated to 60°C and stirred for another 36 h. The mixture was concentrated and the residue was purified by chromatography (silica dioxide, EtOAc/heptane=0-50%) to obtainTitle compound (637.3 mg, 74%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.33 (d, 1H), 7.20 (d, 1H), 6.08 (d, 2H), 5.43 (d, 1H), 5.39 (d, 1H), 3.59-3.46 (m, 5H), 3.30 (s, 3H), 3.20-3.07 (m, 2H), 2.73 (d, 1H), 1.44 (s, 9H), 1.28 (s, 3H), 1.17-1.08 (m, 1H), 0.95-0.88 (m, 2H) , 0.86-0.78 (m, 2H), 0.40 (dd, 1H), 0.27 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

使用3 M K₃ PO₄ (0.71 mL, 2.14 mmol)處理製備物127 (450 mg, 0.71)、乙烯基

酸酐吡啶複合物(258 mg, 1.07 mmol)、Pd(OAc)₂ (8.0 mg, 0.036 mmol)及SPhos (29.3 mg, 0.71 mmol)於1,4-二噁烷(3.6 mL)中之混合物。將混合物在100℃下加熱20 h。過濾混合物並使用EtOAc沖洗固體。使用水稀釋濾液並使用EtOAc (× 3)萃取。乾燥(MgSO₄ )合併之有機萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 0-50%)純化粗製材料以得到標題化合物 (367 mg, 76%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.30 (d, 1H), 7.18 (dd, 1H), 7.15 (s, 1H), 6.62 (dd, 1H), 6.15 (d, 1H), 6.11 (d, 1H), 5.56 (dd, 1H), 5.43 (d, 1H), 5.39 (d, 1H), 3.61-3.49 (m, 5H), 3.31 (s, 3H), 3.18-3.09 (m, 2H), 2.73 (d, 1H), 1.43 (s, 9H), 1.29 (s, 3H), 1.13 (ddd, 1H), 0.91 (ddd, 2H), 0.87-0.79 (m, 2H), 0.41 (dd, 1H), 0.28 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H)。 Preparation 128 : methyl (2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-4- Vinyl -1 H- Benzo [ d ] Imidazole -6- base ) Tert-butyl carbamate

Use 3 M K₃ PO₄ (0.71 mL, 2.14 mmol) treatment preparation 127 (450 mg, 0.71), vinyl

Anhydride pyridine complex (258 mg, 1.07 mmol), Pd(OAc)₂ (8.0 mg, 0.036 mmol) and SPhos (29.3 mg, 0.71 mmol) in 1,4-dioxane (3.6 mL). The mixture was heated at 100°C for 20 h. The mixture was filtered and the solids were rinsed with EtOAc. The filtrate was diluted with water and extracted with EtOAc (×3). Dry (MgSO₄ ) The combined organic extracts are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/heptane=0-50%) to obtainTitle compound (367 mg, 76%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.30 (d, 1H), 7.18 (dd, 1H), 7.15 (s, 1H), 6.62 (dd, 1H), 6.15 (d, 1H), 6.11 (d, 1H), 5.56 (dd, 1H) , 5.43 (d, 1H), 5.39 (d, 1H), 3.61-3.49 (m, 5H), 3.31 (s, 3H), 3.18-3.09 (m, 2H), 2.73 (d, 1H), 1.43 (s , 9H), 1.29 (s, 3H), 1.13 (ddd, 1H), 0.91 (ddd, 2H), 0.87-0.79 (m, 2H), 0.41 (dd, 1H), 0.28 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

使用OsO₄ (4 wt%於水中，5.1 mL, 0.81 mmol)在0℃下處理製備物128 (366 mg, 0.54 mmol)於吡啶(2.7 mL)及THF (2.7 mL)中之溶液。將混合物在0℃下攪拌2 h且然後在室溫下再攪拌18 h。使用10% NaHSO₃ 水溶液(15 mL)處理混合物並在室溫下攪拌3 h。濃縮混合物並使用DCM (× 4)萃取。乾燥(Na₂ SO₄ )合併之有機萃取物，過濾並濃縮。將此殘餘物溶於2:1 THF/水(6 mL)中，冷卻至0℃並使用NaIO₄ (138 mg, 0.65 mmol)處理。將混合物在0℃下攪拌2.5 h。經由矽藻土及MgSO₄ 過濾混合物且濃縮濾液。藉由層析(二氧化矽，EtOAc/庚烷= 10-50%梯度)純化殘餘物以得到標題化合物 (163 mg, 44%)。¹ H NMR (400 MHz, CDCl₃ ) δ 10.92 (s, 1H), 7.77-7.56 (m, 2H), 6.19 (d, 1H), 6.15 (d, 1H), 5.45 (d, 1H), 5.40 (d, 1H), 3.64-3.48 (m, 5H), 3.34 (s, 3H), 3.13 (dd, 2H), 2.74 (d, 1H), 1.44 (s, 9H), 1.29 (s, 3H), 1.21-1.08 (m, 1H), 0.91 (ddd, 2H), 0.87-0.80 (m, 2H), 0.42 (dd, 1H), 0.28 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H)。 Preparation 129 : (4- Formaldehyde -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )( methyl ) Tert-butyl carbamate

Use OsO₄ (4 wt% in water, 5.1 mL, 0.81 mmol) A solution of preparation 128 (366 mg, 0.54 mmol) in pyridine (2.7 mL) and THF (2.7 mL) was treated at 0°C. The mixture was stirred at 0°C for 2 h and then at room temperature for another 18 h. Use 10% NaHSO₃ The mixture was treated with an aqueous solution (15 mL) and stirred at room temperature for 3 h. The mixture was concentrated and extracted with DCM (×4). Dry (Na₂ SO₄ ) The combined organic extracts are filtered and concentrated. Dissolve this residue in 2:1 THF/water (6 mL), cool to 0°C and use NaIO₄ (138 mg, 0.65 mmol) treatment. The mixture was stirred at 0°C for 2.5 h. Via diatomaceous earth and MgSO₄ The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/heptane = 10-50% gradient) to obtainTitle compound (163 mg, 44%).¹ H NMR (400 MHz, CDCl₃ ) δ 10.92 (s, 1H), 7.77-7.56 (m, 2H), 6.19 (d, 1H), 6.15 (d, 1H), 5.45 (d, 1H), 5.40 (d, 1H), 3.64-3.48 ( m, 5H), 3.34 (s, 3H), 3.13 (dd, 2H), 2.74 (d, 1H), 1.44 (s, 9H), 1.29 (s, 3H), 1.21-1.08 (m, 1H), 0.91 (ddd, 2H), 0.87-0.80 (m, 2H), 0.42 (dd, 1H), 0.28 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

使用NaBH₄ (8 mg, 0.22 mmol)在0℃下處理製備物129 (30 mg, 0.044 mmol)於MeOH (1 mL)中之溶液。將混合物升溫至室溫並攪拌2 h。將混合物冷卻至0℃並使用鹽水及水稀釋。使用DCM (× 3)萃取混合物且乾燥(MgSO₄ )合併之有機層，過濾並濃縮以得到標題化合物 (19 mg, 63%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.36 - 7.30 (m, 1H), 7.00 (s, 1H), 6.20 - 6.03 (m, 2H), 5.46 - 5.35 (m, 2H), 5.12 (d, 2H), 4.63 (s, 1H), 3.65 - 3.49 (m, 4H), 3.42 (d, 1H), 3.30 (s, 3H), 3.12 (d, 2H), 2.73 (d, 1H), 1.44 (s, 9H), 1.28 (s, 3H), 1.12 (dt, 1H), 0.91 (ddd, 2H), 0.88 - 0.78 (m, 2H), 0.41 (dd, 1H), 0.25 (t, 1H), -0.02 (s, 9H), -0.11 (s, 9H)；LC/MSm/z (M+H)⁺ = 684.3。 Preparation 130 : (4-( Hydroxymethyl )-2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )( methyl ) Tert-butyl carbamate

Use NaBH₄ (8 mg, 0.22 mmol) A solution of Preparation 129 (30 mg, 0.044 mmol) in MeOH (1 mL) was treated at 0°C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was cooled to 0°C and diluted with brine and water. The mixture was extracted with DCM (× 3) and dried (MgSO₄ ) Combine the organic layers, filter and concentrate to obtainTitle compound (19 mg, 63%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.36-7.30 (m, 1H), 7.00 (s, 1H), 6.20-6.03 (m, 2H), 5.46-5.35 (m, 2H), 5.12 (d, 2H), 4.63 (s, 1H), 3.65-3.49 (m, 4H), 3.42 (d, 1H), 3.30 (s, 3H), 3.12 (d, 2H), 2.73 (d, 1H), 1.44 (s, 9H), 1.28 (s, 3H) , 1.12 (dt, 1H), 0.91 (ddd, 2H), 0.88-0.78 (m, 2H), 0.41 (dd, 1H), 0.25 (t, 1H), -0.02 (s, 9H), -0.11 (s , 9H); LC/MSm/z (M+H)⁺ = 684.3.

使用2,6-二甲基吡啶(9 mg, 0.083 mmol)及TMSOTf (19 mg, 0.083 mmol)在0℃下處理製備物130 (19 mg, 0.028 mmol)於DCM (1 mL)中之溶液。將混合物在0℃下攪拌2 h並使用NaHCO₃ 飽和水溶液處理。使用DCM (× 3)萃取混合物。乾燥(MgSO₄ )合併之有機層，過濾並濃縮以得到標題化合物 (20 mg，定量)。¹ H NMR (600 MHz, CDCl₃ ) δ 6.77 (d, 1H), 6.58 (d, 1H), 6.08 - 5.87 (m, 2H), 5.46 - 5.32 (m, 2H), 5.18 (s, 2H), 3.64 - 3.51 (m, 3H), 3.47 (ddd, 2H), 3.38 (d, 1H), 3.09 (t, 2H), 2.91 (s, 3H), 2.71 (d, 1H), 1.64 (s, 1H), 1.28 (s, 3H), 1.11 (dq, 1H), 0.98 - 0.88 (m, 2H), 0.87 - 0.76 (m, 2H), 0.38 (dd, 1H), 0.33 - 0.24 (m, 1H), -0.02 (d, 9H), -0.13 (s, 9H)；LC/MSm/z (M+H)⁺ = 584.5。 Preparation 131 : (2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-6-( Methylamino )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -4- base ) Methanol

A solution of preparation 130 (19 mg, 0.028 mmol) in DCM (1 mL) was treated with 2,6-lutidine (9 mg, 0.083 mmol) and TMSOTf (19 mg, 0.083 mmol) at 0°C. Stir the mixture at 0°C for 2 h and use NaHCO₃ Saturated aqueous solution treatment. The mixture was extracted with DCM (×3). Dry (MgSO₄ ) Combine the organic layers, filter and concentrate to obtainTitle compound (20 mg, quantitative).¹ H NMR (600 MHz, CDCl₃ ) δ 6.77 (d, 1H), 6.58 (d, 1H), 6.08-5.87 (m, 2H), 5.46-5.32 (m, 2H), 5.18 (s, 2H), 3.64-3.51 (m, 3H), 3.47 (ddd, 2H), 3.38 (d, 1H), 3.09 (t, 2H), 2.91 (s, 3H), 2.71 (d, 1H), 1.64 (s, 1H), 1.28 (s, 3H), 1.11 (dq, 1H), 0.98-0.88 (m, 2H), 0.87-0.76 (m, 2H), 0.38 (dd, 1H), 0.33-0.24 (m, 1H), -0.02 (d, 9H), -0.13 (s, 9H); LC/MSm/z (M+H)⁺ = 584.5.

使用EDCI (25 mg, 0.13 mmol)處理製備物131 (19 mg, 0.033 mmol)及製備物19 (10 mg, 0.065 mmol)於吡啶(1 mL)中之溶液。將混合物在室溫下攪拌18 h。濃縮混合物且使用水稀釋殘餘物，並使用EtOAc (× 3)萃取。乾燥(MgSO₄ )合併之有機層，過濾並濃縮以得到標題化合物 (21 mg, 90%)。¹ H NMR (600 MHz, CDCl₃ ) δ 7.41 - 7.29 (m, 1H), 6.99 (s, 1H), 6.14 (s, 2H), 5.50 - 5.33 (m, 2H), 5.25 - 5.03 (m, 2H), 4.55 (s, 1H), 3.64 (dd, 3H), 3.60 - 3.50 (m, 4H), 3.43 (d, 1H), 3.32 (s, 3H), 3.23 (d, 1H), 3.13 (dd, 2H), 2.74 (d, 1H), 2.63 - 2.47 (m, 3H), 2.37 (dt, 2H), 1.29 (s, 3H), 1.15 (d, 3H), 1.14 - 1.08 (m, 1H), 0.92 (td, 2H), 0.83 (dq, 2H), 0.43 (dd, 1H), 0.25 (t, 1H), -0.02 (d, 9H), -0.11 (d, 9H)；LC/MSm/z (M+H)⁺ = 725.7。 Preparation 132 (S)- N -(4-( Hydroxymethyl )-2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 131 (19 mg, 0.033 mmol) and Preparation 19 (10 mg, 0.065 mmol) in pyridine (1 mL) was treated with EDCI (25 mg, 0.13 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc (×3). Dry (MgSO₄ ) Combine the organic layers, filter and concentrate to obtainTitle compound (21 mg, 90%).¹ H NMR (600 MHz, CDCl₃ ) δ 7.41-7.29 (m, 1H), 6.99 (s, 1H), 6.14 (s, 2H), 5.50-5.33 (m, 2H), 5.25-5.03 (m, 2H), 4.55 (s, 1H), 3.64 (dd, 3H), 3.60-3.50 (m, 4H), 3.43 (d, 1H), 3.32 (s, 3H), 3.23 (d, 1H), 3.13 (dd, 2H), 2.74 (d, 1H) , 2.63-2.47 (m, 3H), 2.37 (dt, 2H), 1.29 (s, 3H), 1.15 (d, 3H), 1.14-1.08 (m, 1H), 0.92 (td, 2H), 0.83 (dq , 2H), 0.43 (dd, 1H), 0.25 (t, 1H), -0.02 (d, 9H), -0.11 (d, 9H); LC/MSm/z (M+H)⁺ = 725.7.

使用鐵粉(9.68 g, 173 mmol)處理1,2-二氟-3-甲基-4-硝基苯(5 g, 28.9 mmol)於AcOH (150 mL)中之溶液並將混合物在室溫下攪拌16 h。過濾反應液且濃縮濾液。將殘餘物溶解於EtOAc (300 mL)中並使用NaHCO₃ (500 mL)飽和水溶液洗滌。乾燥(Na₂ SO₄ )有機層，過濾並在減壓下濃縮以得到標題化合物 (3.8 g, 92%)。LC/MSm/z (M+H)⁺ = 143.8。 Preparation 133 : 3,4- Difluoro -2- Methylaniline

Use iron powder (9.68 g, 173 mmol) to treat a solution of 1,2-difluoro-3-methyl-4-nitrobenzene (5 g, 28.9 mmol) in AcOH (150 mL) and keep the mixture at room temperature Stir for 16 h. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (300 mL) and NaHCO was used₃ (500 mL) Wash with saturated aqueous solution. Dry (Na₂ SO₄ ) The organic layer is filtered and concentrated under reduced pressure to obtainTitle compound (3.8 g, 92%). LC/MSm/z (M+H)⁺ = 143.8.

使用EDCI (10.2 g, 53.1 mmol)處理製備物133 (3.8 g, 26.6 mmol)及製備物19 (8.45 g, 53.1 mmol)於吡啶(200 mL)中之溶液。將混合物在室溫下攪拌16 h。濃縮混合物且使用水稀釋殘餘物，並使用EtOAc (× 3)萃取。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-30%)純化粗製材料以得到標題化合物 (6.9 g, 91%)。LC/MSm/z (M+H)⁺ = 284.9。 Preparation 134 : (S)- N -(3,4- Difluoro -2- Methyl phenyl )-2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 133 (3.8 g, 26.6 mmol) and Preparation 19 (8.45 g, 53.1 mmol) in pyridine (200 mL) was treated with EDCI (10.2 g, 53.1 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc (×3). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-30%) to obtainTitle compound (6.9 g, 91%). LC/MSm/z (M+H)⁺ = 284.9.

使用NaH (1.94 g, 48.5 mmol)在0℃下處理製備物134 (6.9 g, 24.3 mmol)於THF (150 mL)中之溶液。將混合物攪拌30 min且添加碘甲烷(5.17 g, 36.4 mmol)。將混合物升溫至20℃並攪拌16 h。使用水處理混合物並使用EtOAc (2 × 100 mL)萃取。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-60%)純化粗製材料以得到標題化合物 (6.6 g, 91%)。LC/MSm/z (M+H)⁺ = 298.9。 Preparation 135 (S)- N -(3,4- Difluoro -2- Methyl phenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 134 (6.9 g, 24.3 mmol) in THF (150 mL) was treated with NaH (1.94 g, 48.5 mmol) at 0°C. The mixture was stirred for 30 min and methyl iodide (5.17 g, 36.4 mmol) was added. The mixture was warmed to 20°C and stirred for 16 h. The mixture was treated with water and extracted with EtOAc (2×100 mL). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-60%) to obtainTitle compound (6.6 g, 91%). LC/MSm/z (M+H)⁺ = 298.9.

使用濃HNO₃ (2.11 g, 33.5 mmol)在5-10℃下逐滴處理製備物135 (5 g, 16.8 mmol)於濃H₂ SO₄ (40 mL)中之溶液。將混合物在5-10℃下攪拌2 h並傾倒於冰上。使用Na₂ CO₃ 飽和水溶液將pH調節至7且使用EtOAc (2 × 100 mL)萃取混合物。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-40%)純化粗製材料以得到標題化合物 136 (3.5 g, 61%)。LC/MSm/z (M+H)⁺ = 344.1。 Preparation 136 : (S)- N -(3,4- Difluoro -2- methyl -5- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use concentrated HNO₃ (2.11 g, 33.5 mmol) was treated dropwise at 5-10℃ of preparation 135 (5 g, 16.8 mmol) in concentrated H₂ SO₄ (40 mL) in the solution. The mixture was stirred at 5-10°C for 2 h and poured on ice. Use Na₂ CO₃ The pH was adjusted to 7 with saturated aqueous solution and the mixture was extracted with EtOAc (2×100 mL). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-40%) to obtainTitle compound 136 (3.5 g, 61%). LC/MSm/z (M+H)⁺ = 344.1.

使用濃NH₄ OH (40 mL)在20℃下處理製備物136 (3.5 g, 10.2 mmol)於THF (40 mL)中之溶液。將混合物攪拌16 h。使用EtOAc (2 × 200 mL)萃取混合物。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗製材料以得到標題化合物 137 (2.2 g, 63%)。LC/MSm/z (M+H)⁺ = 341.0。 Preparation 137 : (S)- N -(4- Amino -3- fluorine -2- methyl -5- Nitrophenyl )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use concentrated NH₄ A solution of Preparation 136 (3.5 g, 10.2 mmol) in THF (40 mL) was treated with OH (40 mL) at 20°C. The mixture was stirred for 16 h. The mixture was extracted with EtOAc (2×200 mL). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound 137 (2.2 g, 63%). LC/MSm/z (M+H)⁺ = 341.0.

使用鐵粉(2.17 g, 38.8 mmol)處理製備物137 (2.2 g, 6.5 mmol)於AcOH (60 mL)中之溶液並將混合物在室溫下攪拌16 h。過濾混合物且濃縮濾液。將殘餘物溶解於EtOAc (100 mL)中並使用NaHCO₃ (30 mL)飽和水溶液洗滌。乾燥(Na₂ SO₄ )有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%，然後0-10% MeOH/DCM梯度)純化粗製材料以得到標題化合物 (1.3 g, 65%)。LC/MSm/z (M+H)⁺ = 311.1。 Preparation 138 : (S)- N -(4,5- Diamine group -3- fluorine -2- Methyl phenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide )

A solution of preparation 137 (2.2 g, 6.5 mmol) in AcOH (60 mL) was treated with iron powder (2.17 g, 38.8 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (100 mL) and NaHCO was used₃ (30 mL) Wash with saturated aqueous solution. Dry (Na₂ SO₄ ) Organic layer, filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%, then 0-10% MeOH/DCM gradient) to obtainTitle compound (1.3 g, 65%). LC/MSm/z (M+H)⁺ = 311.1.

使用濃NH₄ OH (100 mL)在20℃下處理1,3-二氟-2-甲基-4-硝基苯(5 g, 28.9 mmol)於THF (100 mL)中之溶液。將混合物在室溫下攪拌16 h。使用EtOAc (2 × 200 mL)萃取混合物。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-15%)純化粗製材料以得到標題化合物 (3 g, 61%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.07 (dd, 1H), 6.46 (dd, 1H), 6.32 (s, 2H), 2.13 (d, 3H)。 Preparation 139 : 3- fluorine -2- methyl -6- Nitroaniline

Use concentrated NH₄ A solution of 1,3-difluoro-2-methyl-4-nitrobenzene (5 g, 28.9 mmol) in THF (100 mL) was treated with OH (100 mL) at 20°C. The mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc (2×200 mL). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-15%) to obtainTitle compound (3 g, 61%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.07 (dd, 1H), 6.46 (dd, 1H), 6.32 (s, 2H), 2.13 (d, 3H).

使用N -溴琥珀醯亞胺(3.77 g, 21.2 mmol)在20℃下處理製備物139 (3 g, 07.6 mmol)於MeCN (20 mL)中之溶液。將混合物在90℃下攪拌2 h。將混合物冷卻至室溫並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-15%)純化殘餘物以得到標題化合物 (4.3 g, 98%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.31 (d, 1H), 6.31 (s, 2H), 2.18 (dd, 3H)。 Preparation 140 : 4- bromine -3- fluorine -2- methyl -6- Nitroaniline

useN -Bromosuccinimide (3.77 g, 21.2 mmol) was treated with a solution of Preparation 139 (3 g, 07.6 mmol) in MeCN (20 mL) at 20°C. The mixture was stirred at 90°C for 2 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-15%) to obtainTitle compound (4.3 g, 98%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.31 (d, 1H), 6.31 (s, 2H), 2.18 (dd, 3H).

使用鐵粉(5.79 g, 104 mmol)處理製備物140 (4.3 g, 17.3 mmol)於AcOH (100 mL)中之溶液且將混合物在室溫下攪拌1 h。過濾反應液並濃縮濾液。將殘餘物溶解於EtOAc (300 mL)中並使用NaHCO₃ 飽和水溶液(50 mL)洗滌。乾燥(Na₂ SO₄ )有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-35%)純化粗製材料以得到標題化合物 141 (3.44 g, 91%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.74 (d, 1H), 3.36 (s, 4H), 2.12 (d, 3H)。 Preparation 141 : 5- bromine -4- fluorine -3- Methylbenzene -1,2- Diamine

A solution of preparation 140 (4.3 g, 17.3 mmol) in AcOH (100 mL) was treated with iron powder (5.79 g, 104 mmol) and the mixture was stirred at room temperature for 1 h. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (300 mL) and NaHCO was used₃ Wash with saturated aqueous solution (50 mL). Dry (Na₂ SO₄ ) Organic layer, filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-35%) to obtainTitle compound 141 (3.44 g, 91%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.74 (d, 1H), 3.36 (s, 4H), 2.12 (d, 3H).

使用DAST (0.047 mL, 0.35 mmol)在0℃下處理製備物129 (160 mg, 0.24 mmol)於無水DCE (1.5 mL)中之溶液。將混合物升溫至室溫並攪拌18 h。使用NaHCO₃ 飽和水溶液處理混合物。添加額外水且使用DCM (× 3)萃取混合物。乾燥(MgSO₄ )合併之有機層，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-40%)純化粗製材料以得到標題化合物 (86.0 mg, 52%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.51 (s, 1H), 7.43 (dd, 1H), 7.42 (s, 1H), 6.14 (d, 1H), 6.10 (d, 1H), 5.44 (d, 1H), 5.39 (d, 1H), 3.61-3.50 (m, 4H), 3.48 (d, 1H), 3.34 (s, 3H), 3.17 - 3.05 (m, 2H), 2.73 (d, 1H), 1.44 (s, 9H), 1.29 (s, 3H), 1.13 (ddd, 1H), 0.91 (ddd, 2H), 0.87-0.79 (m, 2H), 0.41 (dd, 1H), 0.27 (dd, 1H), -0.02 (s, 9H), -0.11 (s, 9H)。 Preparation 142 : (4-( Difluoromethyl )-2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )( methyl ) Tert-butyl carbamate

A solution of Preparation 129 (160 mg, 0.24 mmol) in anhydrous DCE (1.5 mL) was treated with DAST (0.047 mL, 0.35 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 18 h. Use NaHCO₃ The mixture was treated with saturated aqueous solution. Additional water was added and the mixture was extracted with DCM (×3). Dry (MgSO₄ ) The combined organic layers are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-40%) to obtainTitle compound (86.0 mg, 52%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.51 (s, 1H), 7.43 (dd, 1H), 7.42 (s, 1H), 6.14 (d, 1H), 6.10 (d, 1H), 5.44 (d, 1H), 5.39 (d, 1H) , 3.61-3.50 (m, 4H), 3.48 (d, 1H), 3.34 (s, 3H), 3.17-3.05 (m, 2H), 2.73 (d, 1H), 1.44 (s, 9H), 1.29 (s , 3H), 1.13 (ddd, 1H), 0.91 (ddd, 2H), 0.87-0.79 (m, 2H), 0.41 (dd, 1H), 0.27 (dd, 1H), -0.02 (s, 9H),- 0.11 (s, 9H).

使用2,6-二甲基吡啶(0.042 mL, 0.36 mmol)在0℃下處理製備物142 (85 mg, 0.12 mmol)於DCM (1 mL)中之溶液，隨後使用TMSOTf (0.066 mL, 0.36 mmol)處理。將混合物在0℃下攪拌2 h。使用NaHCO₃ 飽和水溶液處理混合物。分離有機相且使用額外DCM (× 4)萃取水層。乾燥(MgSO₄ )合併之有機萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化粗製材料以得到標題化合物 (61.9 mg, 85%)。LC/MSm/z (M+H)⁺ = 604.5。 Preparation 143 : 4-( Difluoromethyl )- N- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- amine

A solution of Preparation 142 (85 mg, 0.12 mmol) in DCM (1 mL) was treated with 2,6-lutidine (0.042 mL, 0.36 mmol) at 0°C, followed by TMSOTf (0.066 mL, 0.36 mmol) )deal with. The mixture was stirred at 0°C for 2 h. Use NaHCO₃ The mixture was treated with saturated aqueous solution. The organic phase was separated and the aqueous layer was extracted with additional DCM (×4). Dry (MgSO₄ ) The combined organic extracts are filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-50%) to obtainTitle compound (61.9 mg, 85%). LC/MSm/z (M+H)⁺ = 604.5.

使用EDCI (48 mg, 0.25 mmol)處理製備物143 (61 mg, 0.10 mmol)及19 (24 mg, 0.15 mmol)於吡啶(1 mL)中之溶液。將混合物在室溫下攪拌18 h。濃縮混合物且將殘餘物溶解於水中，並使用EtOAc (× 3)萃取。乾燥(MgSO₄ )合併之有機層，過濾並濃縮以得到標題化合物 (72 mg, 96%)。LC/MSm/z (M+H)⁺ = 745.7。 Preparation 144 : (S)- N -(4-( Difluoromethyl )-2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of preparations 143 (61 mg, 0.10 mmol) and 19 (24 mg, 0.15 mmol) in pyridine (1 mL) was treated with EDCI (48 mg, 0.25 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was dissolved in water and extracted with EtOAc (×3). Dry (MgSO₄ ) Combine the organic layers, filter and concentrate to obtainTitle compound (72 mg, 96%). LC/MSm/z (M+H)⁺ = 745.7.

使用1M KOtBu/THF (31.4 mL, 31.4 mmol)在0℃下處理2-甲氧基乙醇(2.39 g, 31.4 mmol)於THF (40 mL)中之溶液。在30 min之後，添加2,4-二氟-1-硝基苯(5.0 g, 31.4 mmol)於THF (40 mL)中之溶液。將混合物在30℃下攪拌1 h並使用1:1 H₂ O:EtOAc (100 mL)稀釋。分離各層且使用EtOAc (50 mL)萃取水層。乾燥有機萃取物，過濾並濃縮以得到標題化合物 (6.76 g, 100%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.93 (dd, 1H), 6.82 (dd, 1H), 6.72 (ddd, 1H), 4.29 – 4.15 (m, 2H), 3.87 – 3.73 (m, 2H), 3.45 (s, 3H)。 Preparation 145 : 4- fluorine -2-(2- Methoxyethoxy )-1- Nitrobenzene

A solution of 2-methoxyethanol (2.39 g, 31.4 mmol) in THF (40 mL) was treated with 1M KOtBu/THF (31.4 mL, 31.4 mmol) at 0°C. After 30 min, a solution of 2,4-difluoro-1-nitrobenzene (5.0 g, 31.4 mmol) in THF (40 mL) was added. Stir the mixture at 30°C for 1 h and use 1:1 H₂ O: Dilute with EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). Dry the organic extract, filter and concentrate to obtainTitle compound (6.76 g, 100%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.93 (dd, 1H), 6.82 (dd, 1H), 6.72 (ddd, 1H), 4.29 – 4.15 (m, 2H), 3.87 – 3.73 (m, 2H), 3.45 (s, 3H).

使用10% Pd/C (600 mg)處理製備物145 (6.76 g, 31.4 mmol)於MeOH (200 mL)中之溶液，並在H₂ (1 atm)下攪拌16 h。過濾混合物並濃縮濾液以得到標題化合物 (4.53 g, 78%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.66 - 6.48 (m, 3H), 4.16 - 4.06 (m, 2H), 3.81 - 3.66 (m, 2H), 3.44 (s, 3H)。 Preparation 146 : 4- fluorine -2-(2- Methoxyethoxy ) aniline

A solution of preparation 145 (6.76 g, 31.4 mmol) in MeOH (200 mL) was treated with 10% Pd/C (600 mg) and heated in H₂ (1 atm) and stir for 16 h. Filter the mixture and concentrate the filtrate to obtainTitle compound (4.53 g, 78%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.66-6.48 (m, 3H), 4.16-4.06 (m, 2H), 3.81-3.66 (m, 2H), 3.44 (s, 3H).

使用KNO₃ (336 mg, 3.32 mmol)在5℃下處理製備物146 (615 mg, 3.32 mmol)於濃H₂ SO₄ 中之溶液。將混合物攪拌2 h並傾倒至冰水(50 mL)中。使用EtOAc (2 × 40 mL)萃取水性混合物。合併有機萃取物，乾燥，過濾並濃縮以得到標題化合物 (790 mg, 103%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.40 (d, 1H), 6.66 (d, 1H), 4.26 - 4.17 (m, 2H), 3.82 - 3.74 (m, 2H), 3.44 (s, 3H)；LC/MSm/z (M+H)⁺ = 230.9。 Preparation 147 : 4- fluorine -2-(2- Methoxyethoxy )-5- Nitroaniline

Use KNO₃ (336 mg, 3.32 mmol) at 5°C to treat preparation 146 (615 mg, 3.32 mmol) in concentrated H₂ SO₄ In the solution. The mixture was stirred for 2 h and poured into ice water (50 mL). The aqueous mixture was extracted with EtOAc (2×40 mL). The organic extracts are combined, dried, filtered and concentrated to obtainTitle compound (790 mg, 103%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.40 (d, 1H), 6.66 (d, 1H), 4.26-4.17 (m, 2H), 3.82-3.74 (m, 2H), 3.44 (s, 3H); LC/MSm/z (M+H)⁺ = 230.9.

使用EDCI (983 mg, 5.13 mmol)在20℃下處理製備物147 (590 mg, 2.56 mmol)及製備物19 (490 mg, 3.08 mmol)於吡啶(37 mL)中之溶液。將混合物在室溫下攪拌16 h且然後傾倒至水(40 mL)中。使用EtOAc (2 × 40 mL)萃取混合物。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化粗製材料以得到標題化合物 148 (398 mg, 42%)。¹ H NMR (400 MHz, CDCl₃ ) δ 10.01 (s, 1H), 9.29 (d, 1H), 6.76 (d, 1H), 4.33 - 4.21 (m, 2H), 3.91 - 3.78 (m, 6H), 3.46 (s, 3H), 3.27 (q, 1H), 2.72 - 2.50 (m, 4H), 1.34 (d, 3H)；LC/MSm/z (M+H)⁺ = 372.0。 Preparation 148 : (S)- N -(4- fluorine -2-(2- Methoxyethoxy )-5- Nitrophenyl )-2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 147 (590 mg, 2.56 mmol) and Preparation 19 (490 mg, 3.08 mmol) in pyridine (37 mL) was treated with EDCI (983 mg, 5.13 mmol) at 20°C. The mixture was stirred at room temperature for 16 h and then poured into water (40 mL). The mixture was extracted with EtOAc (2×40 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-50%) to obtainTitle compound 148 (398 mg, 42%).¹ H NMR (400 MHz, CDCl₃ ) δ 10.01 (s, 1H), 9.29 (d, 1H), 6.76 (d, 1H), 4.33-4.21 (m, 2H), 3.91-3.78 (m, 6H), 3.46 (s, 3H), 3.27 ( q, 1H), 2.72-2.50 (m, 4H), 1.34 (d, 3H); LC/MSm/z (M+H)⁺ = 372.0.

使用KOtBu (67 mg, 0.59 mmol)在0℃下處理製備物148 (202 mg, 0.54 mmol)於THF (3 mL)中之溶液。在攪拌1 hr之後，添加碘甲烷(84.7 mg, 0.59 mmol)於THF (3 mL)中之溶液並將混合物在室溫下攪拌16 h。使用NH₄ Cl飽和水溶液(15 mL)處理混合物並使用EtOAc (20 mL)萃取混合物。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0- 100%)純化粗製材料以得到標題化合物 (262 mg, 92%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.28 (d, 0.5H), 6.87 (dd, 1H), 4.31 - 4.17 (m, 2H), 3.78 - 3.67 (m, 2H), 3.63 (t, 2H), 3.57 - 3.43 (m, 1H), 3.38 (d, 3H), 3.17 (d, 3H), 2.61 - 2.14 (m, 4H), 1.18 (d, 1.5H), 1.10 (d, 1.5H).；¹⁹ F NMR (376 MHz, CDCl₃ ) δ -111.09。；LC/MSm/z (M+H)⁺ = 386.1。 Preparation 149 : (S)- N -(4- fluorine -2-(2- Methoxyethoxy )-5- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of Preparation 148 (202 mg, 0.54 mmol) in THF (3 mL) was treated with KOtBu (67 mg, 0.59 mmol) at 0°C. After stirring for 1 hr, a solution of methyl iodide (84.7 mg, 0.59 mmol) in THF (3 mL) was added and the mixture was stirred at room temperature for 16 h. Use NH₄ The mixture was treated with saturated aqueous Cl (15 mL) and extracted with EtOAc (20 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (262 mg, 92%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.28 (d, 0.5H), 6.87 (dd, 1H), 4.31-4.17 (m, 2H), 3.78-3.67 (m, 2H), 3.63 (t, 2H), 3.57-3.43 (m, 1H) , 3.38 (d, 3H), 3.17 (d, 3H), 2.61-2.14 (m, 4H), 1.18 (d, 1.5H), 1.10 (d, 1.5H).;¹⁹ F NMR (376 MHz, CDCl₃ ) δ -111.09. ; LC/MSm/z (M+H)⁺ = 386.1.

使用濃NH₄ OH (4.6 g, 130 mmol)在15℃下處理製備物149 (262 mg, 0.68 mmol)於EtOH (5 mL)中之溶液。在50℃下加熱混合物並攪拌16 h。濃縮混合物，使用H₂ O (10 mL)稀釋並使用EtOAc (2 × 10 mL)萃取。使用MeOH:DCM (10 mL:10 mL)進一步萃取水層。合併有機萃取物，乾燥，過濾並濃縮以得到標題化合物 150 (86 mg, 33%)。LC/MSm/z (M+H) = 383.1。 Preparation 150 : (S)- N -(4- Amino -2-(2- Methoxyethoxy )-5- Nitrophenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use concentrated NH₄ A solution of Preparation 149 (262 mg, 0.68 mmol) in EtOH (5 mL) was treated with OH (4.6 g, 130 mmol) at 15°C. The mixture was heated at 50°C and stirred for 16 h. Concentrate the mixture, use H₂ Dilute with O (10 mL) and extract with EtOAc (2 × 10 mL). The aqueous layer was further extracted with MeOH:DCM (10 mL:10 mL). The organic extracts are combined, dried, filtered and concentrated to obtainTitle compound 150 (86 mg, 33%). LC/MSm/z (M+H) = 383.1.

使用10% Pd/C (23.6 mg)處理製備物150 (86 mg, 0.22 mmol)於MeOH (2 mL)中之溶液。使用氬(× 3)將混合物脫氣且然後使用H₂ (3 ×)脫氣。然後將混合物在室溫及H₂ (1 atm)下攪拌20 h。過濾混合物並使用MeOH (3 ×)洗滌固體。收集濾液並濃縮。藉由層析(二氧化矽，EtOH/PE, 0-10%)純化殘餘物以得到標題化合物 151 (71 mg, 73%)。LC/MSm/z (M+H)⁺ = 353.1。 Preparation 151 : (S)- N -(4,5- Diamine group -2-(2- Methoxyethoxy ) Phenyl )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of preparation 150 (86 mg, 0.22 mmol) in MeOH (2 mL) was treated with 10% Pd/C (23.6 mg). Use argon (× 3) to degas the mixture and then use H₂ (3 ×) Degassing. Then put the mixture at room temperature and H₂ (1 atm) and stir for 20 h. The mixture was filtered and the solid was washed with MeOH (3×). The filtrate was collected and concentrated. Purify the residue by chromatography (silica dioxide, EtOH/PE, 0-10%) to obtainTitle compound 151 (71 mg, 73%). LC/MSm/z (M+H)⁺ = 353.1.

使用9 (62 mg, 0.20 mmol)及DMSO (39 mg, 0.50 mmol)處理製備物151 (71 mg, 0.20 mmol)及Na₂ S₂ O₅ (19.1 mg, 0.10 mmol)於DMF (1.0 mL)中之溶液。將混合物在110℃下加熱16 h且然後傾倒至3% LiCl水溶液(5 mL)中。使用EtOAc (10 mL)萃取混合物。收集有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗製材料以得到標題化合物 (160 mg, 120%)。LC/MSm/z (M+H)⁺ = 639.3。 Preparation 152 : (S)- N -(6-(2- Methoxyethoxy )-2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use 9 (62 mg, 0.20 mmol) and DMSO (39 mg, 0.50 mmol) to treat Preparation 151 (71 mg, 0.20 mmol) and Na₂ S₂ O₅ (19.1 mg, 0.10 mmol) in DMF (1.0 mL). The mixture was heated at 110 °C for 16 h and then poured into a 3% LiCl aqueous solution (5 mL). The mixture was extracted with EtOAc (10 mL). Collect organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (160 mg, 120%). LC/MSm/z (M+H)⁺ = 639.3.

使用9 (1.49 g, 4.87 mmol)及DMSO (952 mg, 12.2 mmol)處理5-溴-3-甲基苯-1,2-二胺(980 mg, 4.87 mmol)及Na₂ S₂ O₅ (463 mg, 2.44 mmol)於DMF (24 mL)中之溶液。將混合物在110℃下加熱16 h。將混合物冷卻至室溫並傾倒至3% LiCl (100 mL)水溶液中。藉由過濾收集固體且使用EtOAc (2 × 100 mL)萃取濾液。合併有機層與所收集固體並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-20%)純化殘餘物以得到標題化合物 (2.17 g, 91%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.57 (s, 1H), 7.17 (dd, 1H), 5.58 - 5.40 (m, 2H), 3.61 (dd, 2H), 3.38 (d, 1H), 3.26 - 3.02 (m, 2H), 2.82 - 2.68 (m, 1H), 2.58 (s, 3H), 1.30 (s, 3H), 1.17 (dt, 1H), 0.96 - 0.78 (m, 2H), 0.43 (dd, 1H), 0.26 (t, 1H), -0.04 (s, 9H)；LC/MSm/z (M+H)⁺ = 488.8。 Preparation 153 : (4a S ,5a R )-3-(5- bromine -7- methyl -1 H- Benzo [d] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole

Use 9 (1.49 g, 4.87 mmol) and DMSO (952 mg, 12.2 mmol) 5-bromo-3-methylbenzene-1,2-diamine (980 mg, 4.87 mmol) and Na₂ S₂ O₅ (463 mg, 2.44 mmol) in DMF (24 mL). The mixture was heated at 110°C for 16 h. The mixture was cooled to room temperature and poured into a 3% LiCl (100 mL) aqueous solution. The solid was collected by filtration and the filtrate was extracted with EtOAc (2×100 mL). The organic layer and the collected solids were combined and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound (2.17 g, 91%).¹ H NMR (400 MHz, CD₃ OD) δ 7.57 (s, 1H), 7.17 (dd, 1H), 5.58-5.40 (m, 2H), 3.61 (dd, 2H), 3.38 (d, 1H), 3.26-3.02 (m, 2H), 2.82 -2.68 (m, 1H), 2.58 (s, 3H), 1.30 (s, 3H), 1.17 (dt, 1H), 0.96-0.78 (m, 2H), 0.43 (dd, 1H), 0.26 (t, 1H) ), -0.04 (s, 9H); LC/MSm/z (M+H)⁺ = 488.8.

使用NaH (184 mg, 4.6 mmol)在0℃下處理製備物153 (1.87 g, 3.84 mmol)於THF (38 mL)中之溶液且將混合物攪拌30 min。添加SEM-Cl (703 mg, 4.22 mmol)且將混合物升溫至室溫，並攪拌2.5 h。將反應液冷卻至5℃並使用NH₄ Cl飽和水溶液(20 mL)處理。使用EtOAc萃取混合物且濃縮有機層。藉由層析(二氧化矽，EtOAc/PE = 0-10%)純化殘餘物以得到標題化合物 154 (2.4 g, 92%)。LC/MSm/z (M+H)⁺ = 618.9。 Preparation 154 : (4a S ,5a R )-3-(6- bromine -4- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -2- base )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole

A solution of preparation 153 (1.87 g, 3.84 mmol) in THF (38 mL) was treated with NaH (184 mg, 4.6 mmol) at 0°C and the mixture was stirred for 30 min. SEM-Cl (703 mg, 4.22 mmol) was added and the mixture was warmed to room temperature and stirred for 2.5 h. Cool the reaction solution to 5°C and use NH₄ Treatment with saturated aqueous Cl (20 mL). The mixture was extracted with EtOAc and the organic layer was concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-10%) to obtainTitle compound 154 (2.4 g, 92%). LC/MSm/z (M+H)⁺ = 618.9.

使用胺基甲酸第三丁基酯(182 mg, 1.55 mmol)、Cs₂ CO₃ (844 mg, 2.59 mmol)、QPhos (184 mg, 0.26 mmol)及Pd₂ (dba)₃ (59 mg, 0.065 mmol)處理製備物154 (800 mg, 1.29 mmol)於第三戊基醇(13 mL)中之溶液。將混合物在100℃下加熱16 h。將混合物冷卻至室溫並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-20%)純化殘餘物以得到標題化合物 (500 mg, 59%)。LC/MSm/z (M+H)⁺ = 654.0。 Preparation 155 : (4- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base ) Tert-butyl carbamate

Use t-butyl carbamate (182 mg, 1.55 mmol), Cs₂ CO₃ (844 mg, 2.59 mmol), QPhos (184 mg, 0.26 mmol) and Pd₂ (dba)₃ (59 mg, 0.065 mmol) A solution of Preparation 154 (800 mg, 1.29 mmol) in tertiary amyl alcohol (13 mL) was treated. The mixture was heated at 100°C for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound (500 mg, 59%). LC/MSm/z (M+H)⁺ = 654.0.

使用NaH (122 mg, 3.1 mmol)在0℃下處理製備物155 (500 mg, 0.77 mmol)於THF (11 mL)中之溶液。將混合物攪拌30 min且添加碘甲烷(130 mg, 0.92 mmol)。將混合物升溫至15℃並攪拌16 h。使用NH₄ Cl飽和水溶液處理混合物並使用EtOAc (2 × 10 mL)萃取。濃縮合併之有機層。藉由層析(二氧化矽，EtOAc/PE = 0-20%)純化殘餘物以得到標題化合物 (308 mg, 74%)。LC/MSm/z (M+H)⁺ = 668.0。 Preparation 156 : methyl (4- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base ) Tert-butyl carbamate

A solution of Preparation 155 (500 mg, 0.77 mmol) in THF (11 mL) was treated with NaH (122 mg, 3.1 mmol) at 0°C. The mixture was stirred for 30 min and methyl iodide (130 mg, 0.92 mmol) was added. The mixture was warmed to 15°C and stirred for 16 h. Use NH₄ The mixture was treated with saturated aqueous Cl and extracted with EtOAc (2×10 mL). The combined organic layer was concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-20%) to obtainTitle compound (308 mg, 74%). LC/MSm/z (M+H)⁺ = 668.0.

使用ZnBr₂ (641 mg, 2.84 mmol)在0℃下處理製備物156 (380 mg, 0.57 mmol)於DCM (11 mL)中之溶液。將混合物在室溫下攪拌18 h。將混合物傾倒至NaHCO₃ 飽和水溶液(20 mL)中，並使用DCM (2 × 20 mL)萃取。濃縮合併之有機層以得到標題化合物 (170 mg, 90%)。LC/MSm/z (M+H)⁺ = 567.9。 Preparation 157 : N ,4- Dimethyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- amine

Use ZnBr₂ (641 mg, 2.84 mmol) A solution of Preparation 156 (380 mg, 0.57 mmol) in DCM (11 mL) was treated at 0°C. The mixture was stirred at room temperature for 18 h. Pour the mixture to NaHCO₃ Saturated aqueous solution (20 mL) and extracted with DCM (2×20 mL). Concentrate the combined organic layer to obtainTitle compound (170 mg, 90%). LC/MSm/z (M+H)⁺ = 567.9.

使用EDCI (203 mg, 1.1 mmol)處理製備物157 (300 mg, 0.53 mmol)及製備物19 (124 mg, 0.63 mmol)於吡啶(7.6 mL)中之溶液。將混合物在室溫下攪拌16 h。將混合物分配於水(50 mL)與EtOAc (50 mL)之間。分離有機層並濃縮有機層以得到標題化合物 (380 mg，定量)。LC/MSm/z (M+H)⁺ = 709.0。 Preparation 158 : (S)- N- methyl -N -(4- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -6- base )-2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 157 (300 mg, 0.53 mmol) and Preparation 19 (124 mg, 0.63 mmol) in pyridine (7.6 mL) was treated with EDCI (203 mg, 1.1 mmol). The mixture was stirred at room temperature for 16 h. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). Separate the organic layer and concentrate the organic layer to obtainTitle compound (380 mg, quantitative). LC/MSm/z (M+H)⁺ = 709.0.

在0℃下向2-溴-4-氟苯甲腈(1.0 g, 5.0 mmol)於濃H₂ SO₄ (5.0 mL)中之溶液中逐份添加KNO₃ (556 mg, 5.50 mmol)，且然後在25℃下攪拌2 h。將反應混合物傾倒至冰水中且使用乙酸乙酯(3 × 10 mL)萃取混合物。使用鹽水(10 mL)洗滌合併之有機層，乾燥(Na₂ SO₄ )並濃縮以得到標題化合物 (1.2 g, 98%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.45 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 9.5 Hz, 1H)。 Preparation 159 : 2- bromine -4- fluorine -5- Nitrobenzonitrile

Add 2-bromo-4-fluorobenzonitrile (1.0 g, 5.0 mmol) to concentrated H at 0℃₂ SO₄ (5.0 mL) Add KNO to the solution in portions₃ (556 mg, 5.50 mmol), and then stirred at 25°C for 2 h. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (10 mL) and dried (Na₂ SO₄ ) And condensed to getTitle compound (1.2 g, 98%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.45 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 9.5 Hz, 1H).

在0℃下，向製備物159 (1.10 g, 4.490 mmol)於THF (40 mL)中之溶液中添加濃NH₄ OH (0.63 mL, 4.49 mmol)。將反應液在25℃下攪拌1 h。過濾混合物，並濃縮濾液以得到標題化合物 (1.02 g, 94%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.17 (s, 2H), 7.40 (s, 1H)。 Preparation 160 : 4- Amino -2- bromine -5- Nitrobenzonitrile

At 0°C, to a solution of Preparation 159 (1.10 g, 4.490 mmol) in THF (40 mL) was added concentrated NH₄ OH (0.63 mL, 4.49 mmol). The reaction solution was stirred at 25°C for 1 h. The mixture was filtered, and the filtrate was concentrated to obtainTitle compound (1.02 g, 94%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.17 (s, 2H), 7.40 (s, 1H).

在25℃下，向製備物160 (1.11 g, 4.58 mmol)於EtOH (20 mL)及H₂ O (20 mL)中之溶液中添加NH₄ Cl (1.23 g, 22.9 mmol)，隨後添加鐵粉(1.28 g, 22.9 mmol)。將混合物在25℃下攪拌16h。經由矽藻土過濾反應混合物且使用EtOH (2 × 20 mL)沖洗濾餅，並濃縮濾液。將殘餘物溶於EtOAc中並使用鹽水洗滌，且使用EtOAc (2 × 20 mL)萃取水相，乾燥(Na₂ SO₄ )合併之有機萃取物，過濾並濃縮以得到標題化合物 (860 mg, 88%)。¹ H NMR (400 MHz, CDCl₃ ) δ 6.86 (s, 1H), 6.82 (s, 1H), 3.86 (s, 2H), 3.34 (s, 2H)。 Preparation 161 : 4,5- Diamine group -2- Bromobenzonitrile

At 25 ℃, to the preparation 160 (1.11 g, 4.58 mmol) in EtOH (20 mL) and H₂ Add NH to the solution in O (20 mL)₄ Cl (1.23 g, 22.9 mmol) followed by iron powder (1.28 g, 22.9 mmol). The mixture was stirred at 25°C for 16 h. The reaction mixture was filtered through celite and the filter cake was rinsed with EtOH (2×20 mL), and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with brine, and the aqueous phase was extracted with EtOAc (2 × 20 mL), dried (Na₂ SO₄ ) The combined organic extracts are filtered and concentrated to obtainTitle compound (860 mg, 88%).¹ H NMR (400 MHz, CDCl₃ ) δ 6.86 (s, 1H), 6.82 (s, 1H), 3.86 (s, 2H), 3.34 (s, 2H).

向製備物161 (760 mg, 3.58 mmol)於DMF (15 mL)中之溶液中添加Na₂ S₂ O₅ (341 mg, 1.79 mmol)、DMSO (700 mg, 8.96 mmol)及於DMF (3.0 mL)中之製備物17 (1.21 g, 3.94 mmol)之溶液。將反應混合物在110℃下攪拌16 h，然後濃縮。藉由矽膠層析(二氧化矽，EtOAc/PE = 0-30%)純化粗產物以得到標題化合物 (1.38 g, 68%)。LC/MSm/z (M+H)⁺ = 499.1 Preparation 162 : 6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- Formonitrile

Add Na to a solution of preparation 161 (760 mg, 3.58 mmol) in DMF (15 mL)₂ S₂ O₅ (341 mg, 1.79 mmol), DMSO (700 mg, 8.96 mmol) and a solution of Preparation 17 (1.21 g, 3.94 mmol) in DMF (3.0 mL). The reaction mixture was stirred at 110°C for 16 h, and then concentrated. Purify the crude product by silica gel chromatography (silica dioxide, EtOAc/PE = 0-30%) to obtainTitle compound (1.38 g, 68%). LC/MSm/z (M+H)⁺ = 499.1

在0℃下，向NaH (133 mg, 3.32 mmol)於THF (5.0 mL)中之懸浮液中添加製備物162 (1.380 g, 2.76 mmol)於THF (10 mL)中之溶液。在0℃下攪拌15 min之後，逐滴添加SEM-Cl (0.69 g, 4.15mmol)且將反應混合物在20℃下攪拌2 h。將反應混合物傾倒於冰上且使用EtOAc (3 × 10 mL)萃取混合物。使用鹽水(10 mL)洗滌合併之有機層，乾燥(Na₂ SO₄ )並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-30%)純化粗產物以得到標題化合物 之混合物(1.14 g, 66%)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.08 (d, 1H), 7.93 (d, 1H), 6.23 - 6.11 (m, 2H), 5.50 - 5.38 (m, 2H), 3.68 - 3.50 (m, 4H), 3.49 (m, 1H), 3.21 - 3.07 (m, 2H), 2.77 (d, J = 16.3 Hz, 1H), 1.32 (s, 3H), 1.17 (dt, J = 10.0, 5.5 Hz, 1H), 1.00 - 0.89 (m, 2H), 0.92 - 0.81 (m, 2H), 0.45 (dd, J = 8.8, 4.7 Hz, 1H), 0.28 (t, J = 5.1 Hz, 1H), 0.01 (s, 9H), -0.08 (d, J = 2.7 Hz, 9H)；LC/MSm/z (M+H)⁺ = 629.1。 Preparation 163 : 6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -5- Formonitrile and 5- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -6- Formonitrile

At 0°C, to a suspension of NaH (133 mg, 3.32 mmol) in THF (5.0 mL) was added a solution of Preparation 162 (1.380 g, 2.76 mmol) in THF (10 mL). After stirring at 0°C for 15 min, SEM-Cl (0.69 g, 4.15 mmol) was added dropwise and the reaction mixture was stirred at 20°C for 2 h. The reaction mixture was poured on ice and the mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine (10 mL) and dried (Na₂ SO₄ ) And concentrate. Purify the crude product by chromatography (silica dioxide, EtOAc/PE = 0-30%) to obtainTitle compound The mixture (1.14 g, 66%).¹ H NMR (400 MHz, CDCl₃ ) δ 8.08 (d, 1H), 7.93 (d, 1H), 6.23-6.11 (m, 2H), 5.50-5.38 (m, 2H), 3.68-3.50 (m, 4H), 3.49 (m, 1H), 3.21-3.07 (m, 2H), 2.77 (d, J = 16.3 Hz, 1H), 1.32 (s, 3H), 1.17 (dt, J = 10.0, 5.5 Hz, 1H), 1.00-0.89 (m, 2H) , 0.92-0.81 (m, 2H), 0.45 (dd, J = 8.8, 4.7 Hz, 1H), 0.28 (t, J = 5.1 Hz, 1H), 0.01 (s, 9H), -0.08 (d, J = 2.7 Hz, 9H); LC/MSm/z (M+H)⁺ = 629.1.

使用氮將製備物163 (1.01 g, 1.61 mmol)於DMF (8 mL)中之溶液脫氣。使用N-(2,6-二甲基苯基)-6-羥基吡啶醯胺(156 mg, 0.64 mmol)、K₃ PO₄ (1.02 g, 4.82 mmol)、CuI (153 mg, 0.80 mmol)及2M CH₃ NH₂ /THF (99.8 mg, 3.21 mmol)在20℃下處理溶液。密封反應小瓶並及在110℃下加熱16 h。濃縮反應混合物。藉由層析(二氧化矽，EtOAc/PE = 0-10%)純化粗產物以得到標題化合物 之混合物(670 mg, 68.7%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.87 (s, 0.5H), 7.65 (s, 0.5H), 7.01 (s, 0.5H), 6.67 (s, 0.5H), 6.15 - 6.01 (m, 2H), 5.49 - 5.36 (m, 2H), 4.64 (s, 0H), 3.63 - 3.49 (m, 5H), 3.53 - 3.40 (m, 1H), 3.11 (t, J = 18.0 Hz, 2H), 2.99 (d, J = 5.6 Hz, 3H), 2.75 (d, J = 16.9 Hz, 1H), 1.30 (s, 3H), 1.14 (dt, J = 9.8, 5.3 Hz, 1H), 0.98 - 0.89 (m, 2H), 0.89 - 0.80 (m, 2H), 0.46 - 0.38 (m, 1H), 0.27 (t, J = 5.0 Hz, 1H), -0.00 (d, J = 0.8 Hz, 9H), -0.09 (d, J = 4.3 Hz, 9H)；LC/MSm/z (M+H)⁺ = 579.3。 Preparation 164 : 2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-6-( Methylamino )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -5- Formonitrile and 2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-5-( Methylamino )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -6- Formonitrile

A solution of preparation 163 (1.01 g, 1.61 mmol) in DMF (8 mL) was degassed using nitrogen. Use N-(2,6-dimethylphenyl)-6-hydroxypyridine amide (156 mg, 0.64 mmol), K₃ PO₄ (1.02 g, 4.82 mmol), CuI (153 mg, 0.80 mmol) and 2M CH₃ NH₂ /THF (99.8 mg, 3.21 mmol) The solution was treated at 20°C. The reaction vial was sealed and heated at 110°C for 16 h. The reaction mixture was concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-10%) to obtainTitle compound The mixture (670 mg, 68.7%).¹ H NMR (400 MHz, CDCl₃ ) δ 7.87 (s, 0.5H), 7.65 (s, 0.5H), 7.01 (s, 0.5H), 6.67 (s, 0.5H), 6.15-6.01 (m, 2H), 5.49-5.36 (m, 2H ), 4.64 (s, 0H), 3.63-3.49 (m, 5H), 3.53-3.40 (m, 1H), 3.11 (t, J = 18.0 Hz, 2H), 2.99 (d, J = 5.6 Hz, 3H) , 2.75 (d, J = 16.9 Hz, 1H), 1.30 (s, 3H), 1.14 (dt, J = 9.8, 5.3 Hz, 1H), 0.98-0.89 (m, 2H), 0.89-0.80 (m, 2H ), 0.46-0.38 (m, 1H), 0.27 (t, J = 5.0 Hz, 1H), -0.00 (d, J = 0.8 Hz, 9H), -0.09 (d, J = 4.3 Hz, 9H); LC /MSm/z (M+H)⁺ = 579.3.

在20℃下，向2,3-二胺基-5-溴苯甲酸甲酯(1.57 g, 6.41 mmol)於DMF (30 mL)中之溶液中添加製備物9 (1.96 g, 6.41 mmol)及Na₂ S₂ O₅ (1.2 g, 6.40 mmol)。將混合物在110℃下加熱16 h，然後冷卻至室溫並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-75%)純化粗產物以得到標題化合物 (1.23 g, 36%)。LC/MSm/z (M+H)⁺ = 533.1 (⁸¹ Br)。 Preparation 165 : step 1. 6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -4- Methyl formate

At 20°C, to a solution of 2,3-diamino-5-bromobenzoic acid methyl ester (1.57 g, 6.41 mmol) in DMF (30 mL) was added Preparation 9 (1.96 g, 6.41 mmol) and Na₂ S₂ O₅ (1.2 g, 6.40 mmol). The mixture was heated at 110°C for 16 h, then cooled to room temperature and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-75%) to obtainTitle compound (1.23 g, 36%). LC/MSm/z (M+H)⁺ = 533.1 (⁸¹ Br).

在0℃下，向製備物165 (1.20 g, 2.26 mmol)於THF (50 mL)中之溶液中添加NaH (117 mg, 2.93 mmol)及SEM-Cl (565 mg, 3.39 mmol)。將混合物在室溫下攪拌20 h。使用NH₄ Cl飽和水溶液(1.0 mL)及水(50 mL)處理反應液。使用EtOAc (2 × 150 mL)萃取混合物。使用鹽水洗滌合併之有機萃取物，乾燥(Na₂ SO₄ )並濃縮以得到標題化合物 (1.49 g, 99%)。LC/MSm/z (M+H)⁺ = 663.1 (⁸¹ Br)。 Preparation 166 : 6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -4- Methyl formate

At 0°C, to a solution of preparation 165 (1.20 g, 2.26 mmol) in THF (50 mL) was added NaH (117 mg, 2.93 mmol) and SEM-Cl (565 mg, 3.39 mmol). The mixture was stirred at room temperature for 20 h. Use NH₄ The reaction solution was treated with saturated aqueous Cl (1.0 mL) and water (50 mL). The mixture was extracted with EtOAc (2×150 mL). The combined organic extracts were washed with brine and dried (Na₂ SO₄ ) And condensed to getTitle compound (1.49 g, 99%). LC/MSm/z (M+H)⁺ = 663.1 (⁸¹ Br).

在室溫下，向製備物166 (900 mg, 1.36 mmol)於MeOH (50 mL)中之溶液中添加10% NaOH (5 mL)。將混合物在室溫下攪拌15 h，冷卻至0℃並使用1N HCl酸化至pH約為1。然後使用水(50 mL)稀釋混合物並使用EtOAc (3 × 50 mL)萃取。合併有機萃取物，乾燥(Na₂ SO₄ )並濃縮以得到標題化合物 (880 mg, 100%)。LC/MSm/z (M+H)⁺ = 649.1 (⁸¹ Br)。 Preparation 167 : 6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -4- Formic acid

At room temperature, to a solution of preparation 166 (900 mg, 1.36 mmol) in MeOH (50 mL) was added 10% NaOH (5 mL). The mixture was stirred at room temperature for 15 h, cooled to 0°C and acidified to pH approximately 1 using 1N HCl. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). Combine the organic extracts and dry (Na₂ SO₄ ) And condensed to getTitle compound (880 mg, 100%). LC/MSm/z (M+H)⁺ = 649.1 (⁸¹ Br).

在室溫下，向製備物167 (850 mg, 1.31 mmol)於DMF (10 mL)中之溶液中添加HATU (649 mg, 1.71 mmol)、Et₃ N (1 mL)及NH₄ Cl (211 mg, 3.94 mmol)。將混合物在室溫下攪拌15 h。使用水(50 mL)稀釋混合物並使用EtOAc (3 × 50 mL)萃取。合併有機萃取物，乾燥(Na₂ SO₄ )並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化粗產物以得到標題化合物 (400 mg, 47%)。LC/MSm/z (M+H)⁺ = 648.1 (⁸¹ Br)。 Preparation 168 : 6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -4- Formamide

At room temperature, to a solution of Preparation 167 (850 mg, 1.31 mmol) in DMF (10 mL) was added HATU (649 mg, 1.71 mmol), Et₃ N (1 mL) and NH₄ Cl (211 mg, 3.94 mmol). The mixture was stirred at room temperature for 15 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). Combine the organic extracts and dry (Na₂ SO₄ ) And concentrate. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-50%) to obtainTitle compound (400 mg, 47%). LC/MSm/z (M+H)⁺ = 648.1 (⁸¹ Br).

在0℃下，向製備物168 (400 mg, 0.62 mmol)於THF (20 mL)中之溶液中添加Et₃ N (375 mg, 3.71 mmol)及TFAA (390 mg, 1.86 mmol)。將混合物在室溫下攪拌15 h。使用1:1水/DCM (100 mL)稀釋混合物並分離各層。使用DCM (50 mL)萃取水層。使用鹽水(50 mL)洗滌合併之有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 (389 mg, 100%)。LC/MSm/z (M+H)⁺ = 630.1 (⁸¹ Br)。 Preparation 169 : 6- bromine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -4- Formonitrile

Add Et to a solution of preparation 168 (400 mg, 0.62 mmol) in THF (20 mL) at 0°C₃ N (375 mg, 3.71 mmol) and TFAA (390 mg, 1.86 mmol). The mixture was stirred at room temperature for 15 h. The mixture was diluted with 1:1 water/DCM (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (50 mL). Wash the combined organic extracts with brine (50 mL) and dry (Na₂ SO₄ ), filtered and concentrated to getTitle compound (389 mg, 100%). LC/MSm/z (M+H)⁺ = 630.1 (⁸¹ Br).

在N₂ 下，向製備物169 (389 mg, 0.62 mmol)於第三戊基醇(10 mL)及二噁烷(10 mL)中之溶液中添加胺基甲酸第三丁基酯(217 mg, 1.86 mmol)、Cs₂ CO₃ (403 mg, 1.24 mmol)、tert -BuDavePhos (84.5 mg, 0.25 mmol)及Pd₂ (dba)₃ (57 mg, 0.06 mmol)。將混合物在100℃下攪拌15 h。將反應液冷卻至室溫並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-75%)純化粗產物以得到標題化合物 (320 mg, 78%)。LC/MSm/z (M+H)⁺ = 665.3 Preparation 170 : (4- Cyano -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -6- base ) Tert-butyl carbamate

In N₂ Next, to a solution of Preparation 169 (389 mg, 0.62 mmol) in tertiary amyl alcohol (10 mL) and dioxane (10 mL) was added tert-butyl carbamate (217 mg, 1.86 mmol) ), Cs₂ CO₃ (403 mg, 1.24 mmol),tert -BuDavePhos (84.5 mg, 0.25 mmol) and Pd₂ (dba)₃ (57 mg, 0.06 mmol). The mixture was stirred at 100°C for 15 h. The reaction solution was cooled to room temperature and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-75%) to obtainTitle compound (320 mg, 78%). LC/MSm/z (M+H)⁺ = 665.3

使用ZnBr₂ (914 mg, 4.06 mmol)處理製備物170 (540 mg, 0.81 mmol)於DCM (50 mL)中之溶液。將混合物在室溫下攪拌15 h。過濾反應液且將濾液溶解於DCM (150 mL)中，並使用飽和水溶液NaHCO₃ (50 mL)洗滌。分離各層，並使用DCM (50 mL)萃取水層。使用鹽水洗滌合併之有機萃取物，乾燥(Na₂ SO₄ )過濾並濃縮以得到標題化合物 (155 mg, 34%)。LC/MSm/z (M+H)⁺ = 565.3 Preparation 171 : 6- Amino -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -4- Formonitrile

Use ZnBr₂ (914 mg, 4.06 mmol) A solution of Preparation 170 (540 mg, 0.81 mmol) in DCM (50 mL) was treated. The mixture was stirred at room temperature for 15 h. The reaction solution was filtered and the filtrate was dissolved in DCM (150 mL), and saturated aqueous NaHCO was used₃ (50 mL) Wash. The layers were separated, and the aqueous layer was extracted with DCM (50 mL). The combined organic extracts were washed with brine and dried (Na₂ SO₄ ) Filter and concentrate to getTitle compound (155 mg, 34%). LC/MSm/z (M+H)⁺ = 565.3

在室溫下，向製備物171 (70 mg, 0.12 mmol)於THF (10 mL)中之溶液中添加製備物22 (39 mg, 0.25 mmol)、2-氯-1-甲基吡啶碘化鎓(63 mg, 0.25 mmol)及iPr₂ NEt (80 mg, 0.62 mmol)。將混合物在60℃下攪拌15 h。將反應混合物冷卻至室溫並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗產物以得到標題化合物 (80 mg, 92%)。LC/MSm/z (M+H)⁺ = 705.3 Preparation 172 : (R)-N-(4- Cyano -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -6- base )-2-( Tetrahydro -2H- Pyran -4- base ) Acrylamide

At room temperature, to a solution of Preparation 171 (70 mg, 0.12 mmol) in THF (10 mL) was added Preparation 22 (39 mg, 0.25 mmol), 2-chloro-1-methylpyridinium iodide (63 mg, 0.25 mmol) and iPr₂ NEt (80 mg, 0.62 mmol). The mixture was stirred at 60°C for 15 h. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (80 mg, 92%). LC/MSm/z (M+H)⁺ = 705.3

使用NaH (6.81 mg, 0.17 mmol)在0℃下處理製備物172 (80 mg, 0.11 mmol)於THF (5 mL)中之溶液，且然後使用MeI (24.2 mg, 0.17 mmol)處理。將混合物在室溫下攪拌2 h。使用NH₄ Cl飽和水溶液(0.3 mL)及水(50 mL)處理混合物並使用EtOAc (2 × 50 mL)萃取。使用鹽水洗滌合併之有機萃取物，乾燥(Na₂ SO₄ )並濃縮以得到標題化合物 (82 mg, 100%)。LC/MSm/z (M+H)⁺ = 719.4。 Preparation 173 : (R)-N-(4- Cyano -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -6- base )-N- methyl -2-( Tetrahydro -2H- Pyran -4- base ) Acrylamide

A solution of preparation 172 (80 mg, 0.11 mmol) in THF (5 mL) was treated with NaH (6.81 mg, 0.17 mmol) at 0°C, and then treated with MeI (24.2 mg, 0.17 mmol). The mixture was stirred at room temperature for 2 h. Use NH₄ The mixture was treated with saturated aqueous Cl (0.3 mL) and water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine and dried (Na₂ SO₄ ) And condensed to getTitle compound (82 mg, 100%). LC/MSm/z (M+H)⁺ = 719.4.

步驟 1 ： (S)-N - 甲基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

使用製備物30 (20 g, 65.3 mmol)於DMF (114 mL)中之溶液處理製備物9 (20.2 g, 66.2 mmol)及Na₂ S₂ O₅ (6.2 g, 32.6 mmol)之混合物。使用DMSO (11.6 mL, 163 mmol)處理混合物並在80℃下加熱16 h。將混合物冷卻至室溫並傾倒至冰-水中。使用NaHCO₃ 飽和水溶液將混合物之pH調節至pH 7-8且將混合物再攪拌2 h。藉由過濾收集固體。將固體溶於DCM中，使用鹽水、水洗滌並乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，MeOH/EtOAc = 0-10%)純化粗製材料以得到步驟1之標題化合物 (32.0 g, 85%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.69 - 7.32 (m, 2H), 5.53 - 5.40 (m, 2H), 3.77 - 3.55 (m, 4H), 3.52 - 3.36 (m, 1H), 3.27 - 3.20 (m, 3H), 3.19 - 3.03 (m, 3H), 2.81 - 2.72 (m, 1H), 2.63 - 2.49 (m, 2H), 2.44 - 2.31 (m, 3H), 2.30 - 2.20 (m, 2H), 1.22 - 1.14 (m, 3H), 1.13 - 1.08 (m, 1H), 0.94 - 0.84 (m, 7H), 0.49 - 0.41 (m, 1H), 0.30 - 0.22 (m, 1H), 0.02 - -0.10 (m, 9H)；LC/MSm/z (M+H)⁺ = 579.4。步驟 2 ： (S)-N - 甲基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

將步驟1之矽基醚(30.4 g, 52.6 mmol)於DCM (50 mL)中之溶液冷卻至0℃。經30 min逐滴添加TFA (76.4 mL, 1 mol)於DCM (150 mL)中之預混合溶液。將混合物升溫至室溫且然後攪拌16 h。使用甲苯(100 mL)處理混合物並濃縮。將所得殘餘物與甲苯(2 × 250 mL)共沸。將殘餘物溶於EtOH (210 mL)中，冷卻至0℃並使用濃NH₄ OH (138 mL)經30 min逐滴處理。將混合物升溫至室溫並攪拌2 h。濃縮溶劑並與庚烷(2 × 200 mL)共沸。將殘餘物溶於DCM中並使用1 N HaOH水溶液、鹽水、水依序洗滌，且然後乾燥(MgSO₄ )，過濾並濃縮。將所得固體與二乙醚(× 2)共沸。使用25%水/MeCN (300 mL)使所得固體重結晶，過濾並乾燥以得到結晶白色固體形式之標題化合物 (17.45 g, 74%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.68 - 7.32 (m, 2H), 3.79 - 3.56 (m, 4H), 3.51 - 3.33 (m, 1H), 3.27 - 3.20 (m, 3H), 3.16 - 3.01 (m, 3H), 2.81 - 2.72 (m, 1H), 2.61 - 2.49 (m, 2H), 2.45 - 2.31 (m, 3H), 2.32 - 2.22 (m, 2H), 1.34 - 1.25 (m, 3H), 1.23 - 1.01 (m, 4H), 0.45 - 0.35 (m, 1H), 0.30 - 0.21 (m, 1H)；¹ H NMR (500 MHz, 140℃, DMF-d ₇ ) δ 12.52 (s, 1H), 12.09 (s, 1H), 7.58 (s, 1.5H), 7.46 (s, 0.5H), 3.68 - 3.60 (m, 4H), 3.61 - 3.52 (m, 1H), 3.38 - 3.25 (br, s, 3H), 3.17 (d, 2H), 2.88 (t, 2H), 2.74 - 2.65 (m, 2H), 2.64 - 2.61 (br, s, 3H), 2.43 - 2.31 (m, 2H), 1.41(s, 3H), 1.29 - 1.11 (m, 4H), 0.56 - 0.50 (m, 1H), 0.37 - 0.32 (m, 1H)；SFC方法：Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm，10 - 60% MeOH (含有0.2%異丙胺)/CO_2(g) , 3.0 mL/min，管柱溫度：15℃，滯留時間= 6.59 min (40.9%)及9.54 min (59.1%), 100%ee。LC/MSm/z (M+H)⁺ = 449.1。 Instance Instance 1 : (S)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

step 1 : (S)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 30 (20 g, 65.3 mmol) in DMF (114 mL) was used to treat Preparation 9 (20.2 g, 66.2 mmol) and Na₂ S₂ O₅ (6.2 g, 32.6 mmol) mixture. The mixture was treated with DMSO (11.6 mL, 163 mmol) and heated at 80 °C for 16 h. The mixture was cooled to room temperature and poured into ice-water. Use NaHCO₃ Saturated aqueous solution adjusted the pH of the mixture to pH 7-8 and the mixture was stirred for another 2 h. The solid was collected by filtration. The solid was dissolved in DCM, washed with brine, water and dried (MgSO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, MeOH/EtOAc = 0-10%) to obtain the step 1Title compound (32.0 g, 85%).¹ H NMR (400 MHz, CD₃ OD) δ 7.69-7.32 (m, 2H), 5.53-5.40 (m, 2H), 3.77-3.55 (m, 4H), 3.52-3.36 (m, 1H), 3.27-3.20 (m, 3H), 3.19- 3.03 (m, 3H), 2.81-2.72 (m, 1H), 2.63-2.49 (m, 2H), 2.44-2.31 (m, 3H), 2.30-2.20 (m, 2H), 1.22-1.14 (m, 3H) ), 1.13-1.08 (m, 1H), 0.94-0.84 (m, 7H), 0.49-0.41 (m, 1H), 0.30-0.22 (m, 1H), 0.02--0.10 (m, 9H); LC/ MSm/z (M+H)⁺ = 579.4.step 2 : (S)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

The solution of the silyl ether (30.4 g, 52.6 mmol) from step 1 in DCM (50 mL) was cooled to 0°C. A pre-mixed solution of TFA (76.4 mL, 1 mol) in DCM (150 mL) was added dropwise over 30 min. The mixture was warmed to room temperature and then stirred for 16 h. The mixture was treated with toluene (100 mL) and concentrated. The resulting residue was azeotroped with toluene (2 x 250 mL). Dissolve the residue in EtOH (210 mL), cool to 0°C and use concentrated NH₄ OH (138 mL) was treated dropwise over 30 min. The mixture was warmed to room temperature and stirred for 2 h. The solvent was concentrated and azeotroped with heptane (2 × 200 mL). The residue was dissolved in DCM and washed sequentially with 1 N HaOH aqueous solution, brine, water, and then dried (MgSO₄ ), filtered and concentrated. The obtained solid was azeotroped with diethyl ether (× 2). The resulting solid was recrystallized using 25% water/MeCN (300 mL), filtered and dried to obtain a crystalline white solid formTitle compound (17.45 g, 74%).¹ H NMR (400 MHz, CD₃ OD) δ 7.68-7.32 (m, 2H), 3.79-3.56 (m, 4H), 3.51-3.33 (m, 1H), 3.27-3.20 (m, 3H), 3.16-3.01 (m, 3H), 2.81- 2.72 (m, 1H), 2.61-2.49 (m, 2H), 2.45-2.31 (m, 3H), 2.32-2.22 (m, 2H), 1.34-1.25 (m, 3H), 1.23-1.01 (m, 4H ), 0.45-0.35 (m, 1H), 0.30-0.21 (m, 1H);¹ H NMR (500 MHz, 140℃, DMF-d ₇ ) δ 12.52 (s, 1H), 12.09 (s, 1H), 7.58 (s, 1.5H), 7.46 (s, 0.5H), 3.68-3.60 (m, 4H), 3.61-3.52 (m, 1H), 3.38-3.25 (br, s, 3H), 3.17 (d, 2H), 2.88 (t, 2H), 2.74-2.65 (m, 2H), 2.64-2.61 (br, s, 3H), 2.43-2.31 (m , 2H), 1.41(s, 3H), 1.29-1.11 (m, 4H), 0.56-0.50 (m, 1H), 0.37-0.32 (m, 1H); SFC method: Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm, 10-60% MeOH (with 0.2% isopropylamine)/CO_2(g) , 3.0 mL/min, column temperature: 15℃, retention time = 6.59 min (40.9%) and 9.54 min (59.1%), 100%ee. LC/MSm/z (M+H)⁺ = 449.1.

Instance 1.1 : Dihydrate (S)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide ( Crystal form 1) A solution of the silyl ether (8.90 g, 15.4 mmol) from step 1 of Example 1 in DCM (59 mL) and TFA (29 mL) was stirred for 16 h. The mixture was concentrated and the residue was azeotroped with toluene (2×100 mL). Dissolve the residue in EtOH/concentrated NH₄ OH 3:2 (v/v) mixture (125 mL). The mixture was stirred at room temperature for 2 h. The solvent was concentrated and azeotroped with heptane (2 × 50 mL). The residue was dissolved in DCM and washed sequentially with water and brine. The aqueous phase was extracted with DCM (3 ×) and dried (MgSO₄ ), filtered and concentrated. By SFC (Princeton PPU 250 mm × 50 mm, 5 µm; isocratic elution: 75% CO₂ /25% (0.2% 7N MeOH/MeOH); 80 mL/min) The residue was purified to provide a solid (5.3 g). The solid (5.3 g) was dissolved in DCM (200 mL) and washed with deionized water (2×50 mL). The aqueous layers were combined and extracted with DCM (2×50 mL). Dry (MgSO4) the combined DCM layer, pass through Celite^® Filter, concentrate and dry under vacuum to provide a solid (4.5 g). The solid (4.5 g) was suspended in MeCN (90.4 mL) at room temperature, treated with water (22.3 mL) and the mixture was stirred at 58°C for 1 h until all solids were dissolved. The mixture was cooled to room temperature over 18 h and then stirred at room temperature for 24 h. The solid was collected by filtration and dried under vacuum and 60°C for 60 h to provideTitle compound (3.55 g, 51%).Title compound The NMR is consistent with the NMR of Example 1.powder X Ray diffraction (PXRD) A Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source was used to perform PXRD analysis. Set the divergence slit to 11 mm continuous illumination. The diffracted radiation is detected by the PSD-Lynx Eye detector, where the PSD detector opening is set to 2.949°. The X-ray tube voltage and amperage are set to 40 kV and 40 mA, respectively. In the θ-θ goniometer, when using a step length of 0.016° and a step of 0.3 seconds, data are collected from 3.0° to 40.0° 2θ at the Cu wavelength. Set the anti-scatter screen at a fixed distance of 1.5 mm. The sample was rotated at 15/min during collection. The sample is prepared by placing it in a silicon low background sample holder and rotating during collection. Use Bruker DIFFRAC Plus software to collect data and analyze with EVA diffract plus software. The PXRD data file is not processed before the peak search. Use the peak search algorithm in the EVA software, and use the peak selected to have a threshold of 1 for preliminary peak assignment. To ensure effectiveness, manual adjustment is performed; visually inspect the automatically assigned output and adjust the peak position to the maximum peak. Usually the peak with relative intensity ≥ 3% is selected. Do not select unresolved peaks or peaks consistent with noise. The typical error associated with the peak position of the PXRD as stated in the USP is up to +/- 0.2° 2 θ (USP-941).Title compound The PXRD pattern is provided in Figure 1 and the corresponding peak list can be found in Table 1 below.

Thermogravimetric analysis (TGA) uses Discovery TGA (TA instruments) thermogravimetric analyzer to implement TGA. Weigh approximately 10 mg of the sample into an aluminum pan and heat it from ambient temperature to 250°C at a heating rate of 10°C/min under nitrogen purge (10 mL/min in both the sample chamber and the balance). The TGA of the title compound is provided in Figure 6. For the Form 1 dihydrate, the observed weight loss of 7.4% is consistent with the theoretical weight loss of 7.4%.

Instance 1.2a : Dihydrate (S)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide ( Crystal form 2) The solution of the silyl ether (30.4 g, 52.6 mmol) from step 1 of Example 1 in DCM (50 mL) was cooled to 0°C. A pre-mixed solution of TFA (76.4 mL, 1 mol) in DCM (150 mL) was added dropwise over 30 min. The mixture was warmed to room temperature and then stirred for 16 h. The mixture was treated with toluene (100 mL) and concentrated. The resulting residue was azeotroped with toluene (2 x 250 mL). Dissolve the residue in EtOH (210 mL), cool to 0°C and use concentrated NH₄ OH (138 mL) was treated dropwise over 30 min. The mixture was warmed to room temperature and stirred for 2 h. The solvent was concentrated and azeotroped with heptane (2 × 200 mL). The residue was dissolved in DCM and washed sequentially with 1 N NaOH aqueous solution, brine, water, and then dried (MgSO₄ ), filtered and concentrated. The resulting solid was azeotroped with diethyl ether (×2) to provide a solid (24 g). A suspension of the solids (24 g) in MeCN (240 mL) and water (60 mL) was heated at a temperature between 60°C and 70°C for 30 min. Undissolved solids were removed by filtration and the filtrate was slowly cooled to room temperature. Seed crystals (Example 1.1, Form 1) were added and the mixture was stirred at room temperature for about 24 h. The solid was collected by filtration and dried under vacuum and 50°C to provideTitle compound (17.45 g, 74%).¹ H NMR (400 MHz, CD₃ OD) δ 7.68-7.32 (m, 2H), 3.79-3.56 (m, 4H), 3.51-3.33 (m, 1H), 3.27-3.20 (m, 3H), 3.16-3.01 (m, 3H), 2.81- 2.72 (m, 1H), 2.61-2.49 (m, 2H), 2.45-2.31 (m, 3H), 2.32-2.22 (m, 2H), 1.34-1.25 (m, 3H), 1.23-1.01 (m, 4H ), 0.45-0.35 (m, 1H), 0.30-0.21 (m, 1H);¹ H NMR (500 MHz, 140℃, DMF-d ₇ ) δ 12.52 (s, 1H), 12.09 (s, 1H), 7.58 (s, 1.5H), 7.46 (s, 0.5H), 3.68-3.60 (m, 4H), 3.61-3.52 (m, 1H), 3.38-3.25 (br, s, 3H), 3.17 (d, 2H), 2.88 (t, 2H), 2.74-2.65 (m, 2H), 2.64-2.61 (br, s, 3H), 2.43-2.31 (m , 2H), 1.41(s, 3H), 1.29-1.11 (m, 4H), 0.56-0.50 (m, 1H), 0.37-0.32 (m, 1H); SFC method: Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm, 10-60% MeOH (with 0.2% isopropylamine)/CO_2(g) , 3.0 mL/min, column temperature: 15℃, retention time = 6.59 min (40.9%) and 9.54 min (59.1%), 100%ee. LC/MSm/z (M+H)⁺ = 449.1.

PXRD implements PXRD according to the procedure stated in Example 1.1 (Form 1), but the divergence slit is set at 10 mm, the PSD detector opening is set at 2.99 degrees, and the step size is 0.02°. The PXRD pattern of the title compound is provided in Figure 2 and is consistent with the calculated powder pattern generated from the single crystal solution of Example 1.4 below. The corresponding peak list can be found in Table 1 below.

Instance 1.2b : Dihydrate (S)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide ( Crystal form 2) A 1:1 (v/v) DCM/TFA mixture (342 mL) was used to treat the solution of the silyl ether (70.0 g, 120.9 mmol) in DCM (150 mL) of Example 1 from step 1 dropwise at about 0°C . The reaction mixture was warmed to room temperature and stirred for about 16 h. The mixture was concentrated and the residue was azeotroped with toluene (2×). Dissolve the residue in ethanol (300 mL) and use concentrated NH₄ OH (300 mL) was treated dropwise. The mixture was stirred at room temperature for about 24 h. Concentrate the solvent. The residue was dissolved in DCM and washed sequentially with brine and water. The DCM extract was dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 50-100%, then MeOH/EtOAc 0-3%) to provide a solid (batch 1, 31 g). A solution of the collected solids (2.0 g) in ethanol (12 mL) was heated to about 75°C and water (18 mL) was added at a rate that kept the internal temperature above 70°C. The mixture was cooled to about 60°C and treated with other solids (100 mg). The mixture was stirred at about 60°C for about 2 h and then at about 30°C for about 18 h. The mixture was cooled to about 5°C and stirred for about 1 h. The solid was collected by filtration, rinsed with 1:2 (v/v) ethanol/water and dried to provide the solid (batch 2, 1.1 g). The remaining batch 1 solid (29 g) was suspended in MTBE (150 mL) and stirred at about 30°C for about 48 h. The solid was collected by filtration, rinsed with MTBE and dried to provide the solid (batch 3, 23 g). The combined batch 2 and batch 3 solids (24.1 g) were suspended in ethanol (150 mL) and heated to about 75°C, and water (220 mL) was added at a rate that kept the internal temperature above 70°C. The solution was stirred at about 65°C for about 1 h, at about 55°C for about 1 h, at 45°C for about 3 h, and then at about 35°C for about 48 h. Collect the solid by filtration, rinse with 1:2 (v/v) ethanol/water and dry under vacuum to provideTitle compound (20.5 g, 38%).Title compound The NMR and PXRD are consistent with those of Example 1.2a.

Instance 1.3 : Hemihydrate (S)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide ( Crystal form 3) Dihydrate (S)-N -methyl-N -(6-Methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1H -Benzo[d]imidazol-5-yl)-2-N Suspended in MeCN (4 mL) and stirred for about 18 h at room temperature. The solid was collected by filtration and rinsed with MeCN (approximately 3 mL). The collected solid was dried under vacuum at 50°C for 1.5 h to provide the title compound (300 mg, 89%).

TGA and PXRD Implement TGA and PXRD according to the procedures described in Examples 1.1 (Form 1) and 1.2a (Form 2), respectively.Title compound The PXRD pattern is provided in Figure 3 and the corresponding peak list can be found in Table 1 below.Title compound The TGA is provided in Figure 7. For the form 3 hemihydrate, the observed weight loss of 1.8% is consistent with the theoretical weight loss of 2%.surface 1 PXRD peak list of each crystal form 1, 2 and 3 of Examples 1.1, 1.2a and 1.3 Form 1 Form 2 ^[1] Form 3 Angle, °2θ (°2 West Tower) Relative Strength,% Angle, °2θ (°2 West Tower) Relative Strength,% Angle, °2θ (°2 West Tower) Relative Strength,% 8.6 12 6.6 46 6.8 3 9.2 5 7.4 6 8.5 6 10.1 53 11.0 twenty four 10.6 9 12.6 100 11.6 5 11.1 13 13.7 5 12.4 10 12.0 17 14.4 74 13.3 76 13.0 twenty two 15.0 65 14.4 38 13.5 twenty one 16.2 78 14.8 34 14.5 12 16.8 9 15.2 3 14.9 100 17.0 10 15.7 54 16.4 51 18.6 57 16.2 70 16.8 43 18.9 55 17.0 8 18.5 91 19.4 44 17.2 4 19.6 26 19.9 twenty three 17.7 twenty three 20.5 4 20.3 13 18.2 48 21.1 12 21.0 35 18.8 100 21.6 11 22.1 31 19.9 3 22.5 20 22.5 41 20.6 52 23.4 27 22.9 9 21.6 5 23.8 42 23.5 43 22.4 40 24.6 12 23.9 twenty one 22.9 87 26.0 4 24.6 8 23.6 30 27.3 twenty two 25.7 8 24.0 36 27.7 15 26.0 39 25.0 4 28.6 6 26.4 31 25.5 11 29.0 8 27.2 12 26.0 twenty two 29.9 13 27.6 3 26.7 39 33.9 3 29.2 12 28.0 6 34.5 4 29.4 16 28.4 32 35.4 5 29.8 9 29.1 10 37.4 3 30.7 twenty two 29.9 13 31.2 7 30.7 3 31.8 6 31.1 8 32.7 6 31.5 6 33.6 7 32.0 6 35.0 7 32.6 4 35.4 15 32.9 8 36.4 8 33.3 5 37.7 5 34.4 7 38.3 4 35.7 3 36.9 15 38.1 9 39.4 3 39.5 4 ^[1] The PXRD pattern of formation 2 is consistent with the calculated powder pattern generated from the single crystal solution of Example 1.4 below.

Instance 1.4 : Dihydrate (S)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N - 𠰌 Hydroxypropionamide ( Crystal form 2) In a 20 mL scintillation vial, dihydrate (S)-N -methyl-N -(6-Methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1H -Benzo[d]imidazol-5-yl)-2-N -Propylamine (Form 2) (30 mg) was dissolved in EtOAc (10 mL). Use the cap to close the vial, but do not tighten it. The vial was kept undisturbed at room temperature for approximately 26 days. During the elapsed time, most of the solvent has evaporated and about 1 mL of EtOAc andTitle compound .

Single crystal X Ray diffraction (SXRD) SXRD was performed on the Bruker D8 Venture diffractometer at room temperature. Data acquisition consists of Ω and φ scanning. By inherent phasing using the SHELX software package in the orthorhombic space group P2₁ 2₁ 2₁ Analyze the structure. The structure is then refined by the full matrix least square method. Find all non-hydrogen atoms and refine them using anisotropic displacement parameters. The final R index is 3.92%. The final difference Fourier diagram (difference Fourier) reveals no omissions or ectopic electron density. Table 2 contains the structure data of SXRD analysis.surface 2 Instance 1.4 Crystalline form ( form 2) Crystal structure data Empirical C25 H36 N6 O4 Formula 484.60 temperature 296(2) K wavelength 1.54178 Å Crystal system Orthorhombic crystal Space group P212121 Unit cell size a = 6.6838(2)Å α = 90° b = 16.0450(4) Å β = 90° c = 23.8703(6) Å γ = 90° volume 2559.89(12)Å ³ Z 4 Density (calculated value) 1.257 Mg/m3 Goodness of fit to F ² 1.043 The final R index [I＞2σ(I)] R1 = 0.0392, wR2 = 0.1026 R index (all data) R1 = 0.0451, wR2 = 0.1048 The ORTEP diagram of a molecule in the asymmetric unit of the solution is shown in Figure 4, where the displacement parameter at 50% probability is used and the water molecule is omitted in the figure for clarity. Figure 5 uses the displacement parameter under 50% probability to draw and show the ORTEP diagram of water molecules. In Table 3, a list of the PXRD peaks of the calculated powder pattern of Form 2 is given.surface 3 List of calculated PXRD peaks from SXRD data in Form 2 Angle (2θ) Relative Strength(%) Angle (2θ) Relative Strength(%) 6.6 59 24.0 31 7.4 8 25.0 4 9.2 3 25.5 10 11.0 28 26.0 17 11.6 5 26.6 26 12.4 11 26.7 18 13.3 64 27.0 3 14.3 49 27.9 5 14.8 39 28.3 15 15.2 4 28.4 26 15.7 51 29.1 6 16.2 81 29.2 6 17.0 8 29.9 10 17.3 3 31.1 6 17.7 twenty four 31.5 4 18.2 41 31.8 4 18.5 12 32.0 4 18.8 100 32.6 4 20.6 51 32.9 6 21.6 4 33.3 5 22.1 9 34.4 4 22.3 33 36.9 9 22.5 20 37.0 6 22.9 73 38.1 7 23.0 18 39.5 3 The comparison of the experimental PXRD data in Table 1 of Form 2 (Example 1.2a) and the calculated PXRD pattern data in Table 3 of Form 2 (Example 1.4) obtained from the single crystal structure determination showed good peak correlation.

遵循針對實例1所闡述之程序自製備物31 (292 mg)及製備物9 (306 mg)來製備實例2以提供110 mg標題化合物 。SFC方法：Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm, CO₂ /MeOH (0.2%異丙胺)，5%至60%, 3.0 mL/min，管柱溫度：15℃，滯留時間= 6.33 min (13.42%), 6.74 min (24.37%), 8.35 min (35.92%)及9.76 min (24.37%)；LC/MSm/z (M+H)⁺ = 449.5。 Instance 2 : N - methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N - 𠰌 Hydroxypropionamide

Follow the procedure described for Example 1 from Preparation 31 (292 mg) and Preparation 9 (306 mg) to prepare Example 2 to provide 110 mgTitle compound . SFC method: Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm, CO₂ /MeOH (0.2% isopropylamine), 5% to 60%, 3.0 mL/min, column temperature: 15℃, retention time = 6.33 min (13.42%), 6.74 min (24.37%), 8.35 min (35.92%) And 9.76 min (24.37%); LC/MSm/z (M+H)⁺ = 449.5.

步驟 1 ： (R)-N - 甲基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

將製備物46 (219 mg, 0.5 mmol)、(R)-2-N -𠰌啉基丙酸(398 mg, 2.50 mmol)、EDCI (959 mg, 5.00 mmol)於吡啶(10.0 mL)中之混合物在80℃下加熱16 h。將混合物冷卻至室溫並使用EtOAc/水稀釋。分離有機層並使用NH4Cl飽和水溶液、鹽水依序洗滌，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，0-10% MeOH/EtOAc)純化粗製材料以得到標題化合物 160 (150 mg, 50%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.68 (s, 1H), 7.53 (s, 1H), 5.62 - 5.38 (m, 2H), 3.71 - 3.57 (m, 6H), 3.43 (d, 1H), 3.28 (d, 3H), 3.24 - 3.04 (m, 3H), 2.81 (d, 1H), 2.67 - 2.49 (m, 2H), 2.47 (s, 2H), 2.36 (s, 1H), 2.31 (dd, 2H), 1.34 (d, 4H), 1.22 (d, 2H), 1.13 (dd, 1H), 0.98 - 0.88 (m, 2H), 0.48 (dd, 1H), 0.30 (t, 1H), 0.02 - -0.02 (m, 9H)；LC/MSm/z (M+H)⁺ = 579.6。步驟 2 ： (R)-N - 甲基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

使用Et₃ SiH (151 mg, 1.3 mmol)處理步驟1之矽基醚(150 mg, 0.259 mmol)於TFA (2 mL)中之溶液。將混合物在室溫下攪拌1h。濃縮混合物並使用甲苯(2 × 10 mL)研磨殘餘物。將殘餘物溶於EtOH (8 mL)中並使用濃NH₄ OH (2 mL)處理。將混合物在室溫下攪拌2 h並濃縮。將殘餘物溶於DCM中並使用水及鹽水依序洗滌，乾燥(MgSO₄ )，過濾並濃縮。藉由層析(二氧化矽，MeOH-EtOAc = 0-10%)純化粗製材料以得到標題化合物 (100 mg, 86%)。SFC方法：Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm, CO2/MeOH (0.2%異丙胺)，5%至60%, 3.0 mL/min，管柱溫度：15℃，RT=6.29 min (30.15%)及8.38 min (69.20%), 99.37%ee；¹ H NMR (400 MHz, CD₃ OD) δ 7.65 (s, 1H), 7.51 (s, 1H), 3.70 - 3.56 (m, 4H), 3.42 - 3.34 (m, 1H), 3.26 (d, 3H), 3.19 - 3.02 (m, 3H), 2.79 (d, 1H), 2.64 - 2.49 (m, 2H), 2.45 (s, 2H), 2.35 (s, 1H), 2.34 - 2.22 (m, 2H), 1.31 (s, 3H), 1.25 - 1.15 (m, 2H), 1.12 (d, 2H), 0.44 (dd, 1H), 0.27 (t, 1H)；LC/MSm/z (M+H)⁺ = 449.5。 Instance 3 : (R)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

step 1 : (R)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

The preparation 46 (219 mg, 0.5 mmol), (R)-2-N -A mixture of linolinopropionic acid (398 mg, 2.50 mmol), EDCI (959 mg, 5.00 mmol) in pyridine (10.0 mL) was heated at 80°C for 16 h. The mixture was cooled to room temperature and diluted with EtOAc/water. The organic layer was separated and washed sequentially with saturated aqueous NH4Cl, brine, and dried (MgSO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, 0-10% MeOH/EtOAc) to obtainTitle compound 160 (150 mg, 50%).¹ H NMR (400 MHz, CD₃ OD) δ 7.68 (s, 1H), 7.53 (s, 1H), 5.62-5.38 (m, 2H), 3.71-3.57 (m, 6H), 3.43 (d, 1H), 3.28 (d, 3H), 3.24 -3.04 (m, 3H), 2.81 (d, 1H), 2.67-2.49 (m, 2H), 2.47 (s, 2H), 2.36 (s, 1H), 2.31 (dd, 2H), 1.34 (d, 4H) ), 1.22 (d, 2H), 1.13 (dd, 1H), 0.98-0.88 (m, 2H), 0.48 (dd, 1H), 0.30 (t, 1H), 0.02--0.02 (m, 9H); LC /MSm/z (M+H)⁺ = 579.6.step 2 : (R)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

Use Et₃ SiH (151 mg, 1.3 mmol) was used to treat a solution of the silyl ether (150 mg, 0.259 mmol) of step 1 in TFA (2 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was triturated with toluene (2×10 mL). Dissolve the residue in EtOH (8 mL) and use concentrated NH₄ OH (2 mL) treatment. The mixture was stirred at room temperature for 2 h and concentrated. The residue was dissolved in DCM and washed sequentially with water and brine, and dried (MgSO₄ ), filtered and concentrated. The crude material was purified by chromatography (silica dioxide, MeOH-EtOAc=0-10%) to obtainTitle compound (100 mg, 86%). SFC method: Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm, CO2/MeOH (0.2% isopropylamine), 5% to 60%, 3.0 mL/min, column temperature: 15℃, RT=6.29 min ( 30.15%) and 8.38 min (69.20%), 99.37%ee;¹ H NMR (400 MHz, CD₃ OD) δ 7.65 (s, 1H), 7.51 (s, 1H), 3.70-3.56 (m, 4H), 3.42-3.34 (m, 1H), 3.26 (d, 3H), 3.19-3.02 (m, 3H) , 2.79 (d, 1H), 2.64-2.49 (m, 2H), 2.45 (s, 2H), 2.35 (s, 1H), 2.34-2.22 (m, 2H), 1.31 (s, 3H), 1.25-1.15 (m, 2H), 1.12 (d, 2H), 0.44 (dd, 1H), 0.27 (t, 1H); LC/MSm/z (M+H)⁺ = 449.5.

步驟 1 ： (R)-N- 甲基 -N-(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H- 苯并 [d] 咪唑 -5- 基 )-2-( 四氫 -2H- 吡喃 -4- 基 ) 丙醯胺

使用i Pr₂ NEt (100 µL, 0.55 mmol)、製備物22 (86.8 mg, 0.55 mmol)及2-氯-1-甲基吡啶碘化鎓(140 mg, 0.548 mmol)處理製備物46 (120mg, 0.274 mmol)於THF (5 mL)中之溶液。將混合物在60℃下加熱16 h。添加水(10 mL)並使用EtOAc (2 × 20 mL)萃取混合物。濃縮合併之有機萃取物並藉由矽膠層析(二氧化矽，EtOAc/PE = 0-85%)純化殘餘物以得到標題化合物 (165 mg，定量)。¹ H NMR (400 MHz, CD₃ OD) δ 7.52 (s, 2H), 5.55 - 5.43 (m, 2H), 3.91 (t, 2H), 3.64 (t, 2H), 3.48 - 3.34 (m, 3H), 3.25 (dd, 3H), 3.21 - 3.11 (m, 3H), 2.79 (d, 1H), 2.42 - 2.35 (m, 3H), 2.20 - 2.10 (m, 1H), 2.01 - 1.91 (m, 1H), 1.82 - 1.72 (m, 1H), 1.60 (t, 2H), 1.33 (s, 3H), 1.17 (dd, 1H), 1.12 (d, 1H), 1.06 - 0.99 (m, 2H), 0.95 - 0.85 (m, 2H), 0.46 (dd, 1H), 0.28 (t, 1H), -0.02 (d, 9H)；LC/MSm/z (M+H)⁺ = 578.3。步驟 2 ： (R)-N - 甲基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-( 四氫 -2H - 吡喃 -4- 基 ) 丙醯胺

將步驟1之矽基醚(3.7 g, 6.4 mmol)於TFA (45.7 mL)及Et₃ SiH (3.72 g, 32.0 mmol)中之混合物在室溫下攪拌3 h且濃縮混合物。使用NaHCO₃ 飽和水溶液處理殘餘物直至pH=8並使用EtOAc (2 × 30 mL)萃取。合併萃取物，乾燥(MgSO₄ )，過濾並濃縮。藉由製備型HPLC (YMC triart C18 250 × 50 mm × 7 µM，水(0.05% NH₄ OH)/MeCN，在10 min內26%至66%，60 ml/min)純化粗產物以得到標題化合物 (1.86 g, 64.9%)。SFC方法：Chiral Tech OD-3 100 mm × 4.6 mm × 3 µm, CO₂ /EtOH (0.05%)，5%至40%， 1.5 mL/min，管柱溫度：35℃，滯留時間= 3.47 min (41.5%)及3.55 min (58.5%), 100%ee；¹ H NMR (400 MHz, CD₃ OD) δ 7.52 (s, 2H), 3.99 - 3.66 (m, 2H), 3.46-3.34 (m, 3H), 3.26 (d, 3H), 3.20 - 3.11 (m, 2H), 3.08 (d, 1H), 2.79 (d, 1H), 2.38 (d, 3H), 2.16 (t, 0.5H), 1.99 (dd, 0.5H), 1.78 (ddt, 1H), 1.60 (t, 2H), 1.31 (s, 3H), 1.18 (dt, 1H), 1.12 (d, 1H), 1.07 - 0.95 (m, 3H), 0.43 (dd, 1H), 0.27 (t, 1H)；LC/MSm/z (M+H)⁺ = 448.3。 Instance 4 : (R)-N- methyl -N-(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2H- Pyran -4- base ) Acetamide

step 1 : (R)-N- methyl -N-(6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2H- Pyran -4- base ) Acetamide

usei Pr₂ NEt (100 µL, 0.55 mmol), preparation 22 (86.8 mg, 0.55 mmol) and 2-chloro-1-methylpyridinium iodide (140 mg, 0.548 mmol) were treated with preparation 46 (120 mg, 0.274 mmol) in Solution in THF (5 mL). The mixture was heated at 60°C for 16 h. Water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were concentrated and the residue was purified by silica gel chromatography (silica, EtOAc/PE = 0-85%) to obtainTitle compound (165 mg, quantitative).¹ H NMR (400 MHz, CD₃ OD) δ 7.52 (s, 2H), 5.55-5.43 (m, 2H), 3.91 (t, 2H), 3.64 (t, 2H), 3.48-3.34 (m, 3H), 3.25 (dd, 3H), 3.21 -3.11 (m, 3H), 2.79 (d, 1H), 2.42-2.35 (m, 3H), 2.20-2.10 (m, 1H), 2.01-1.91 (m, 1H), 1.82-1.72 (m, 1H) , 1.60 (t, 2H), 1.33 (s, 3H), 1.17 (dd, 1H), 1.12 (d, 1H), 1.06-0.99 (m, 2H), 0.95-0.85 (m, 2H), 0.46 (dd , 1H), 0.28 (t, 1H), -0.02 (d, 9H); LC/MSm/z (M+H)⁺ = 578.3.step 2 : (R)- N- methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

Put the silyl ether (3.7 g, 6.4 mmol) from step 1 in TFA (45.7 mL) and Et₃ The mixture in SiH (3.72 g, 32.0 mmol) was stirred at room temperature for 3 h and the mixture was concentrated. Use NaHCO₃ The residue was treated with saturated aqueous solution until pH=8 and extracted with EtOAc (2×30 mL). Combine the extracts and dry (MgSO₄ ), filtered and concentrated. By preparative HPLC (YMC triart C18 250 × 50 mm × 7 µM, water (0.05% NH₄ OH)/MeCN, 26% to 66% within 10 min, 60 ml/min) purify the crude product to obtainTitle compound (1.86 g, 64.9%). SFC method: Chiral Tech OD-3 100 mm × 4.6 mm × 3 µm, CO₂ /EtOH (0.05%), 5% to 40%, 1.5 mL/min, column temperature: 35℃, retention time = 3.47 min (41.5%) and 3.55 min (58.5%), 100%ee;¹ H NMR (400 MHz, CD₃ OD) δ 7.52 (s, 2H), 3.99-3.66 (m, 2H), 3.46-3.34 (m, 3H), 3.26 (d, 3H), 3.20-3.11 (m, 2H), 3.08 (d, 1H) , 2.79 (d, 1H), 2.38 (d, 3H), 2.16 (t, 0.5H), 1.99 (dd, 0.5H), 1.78 (ddt, 1H), 1.60 (t, 2H), 1.31 (s, 3H ), 1.18 (dt, 1H), 1.12 (d, 1H), 1.07-0.95 (m, 3H), 0.43 (dd, 1H), 0.27 (t, 1H); LC/MSm/z (M+H)⁺ = 448.3.

類似於實例4自製備物46 (100 mg)及72 mg (±)-2-(四氫-2H -吡喃-4-基)丙酸來製備實例5並藉由製備型HPLC (Phenomenex Gemini-NX C18 150 mm × 30 mm × 5 µM，水(0.04% NH₄ OH)/MeCN，在9 min內26%至66%，25 ml/min)純化以得到標題化合物 (63 mg, 51%)。SFC方法：Chiral Tech OD-3 100 mm × 4.6 mm × 3 µm, CO₂ /EtOH (0.05% )，5%至40%，2.8 mL/min，管柱溫度：35℃，滯留時間= 3.39 min (15.8%), 3.46 min (26.0%), 3.54 min (35.6%)及3.76 min (22.43%)；¹ H NMR (400 MHz, CD₃ OD) δ 7.57 (d, 1H), 7.47 (d, 1H), 4.00 - 3.80 (m, 2H), 3.47 - 3.35 (m, 4H), 3.29 - 3.22 (m, 3H), 3.15 (dd, 1H), 3.08 (d, 1H), 2.79 (d, 1H), 2.38 (d, 3H), 2.16 (dd, 0.5H), 1.99 (t, 0.5H), 1.90 - 1.69 (m, 1H), 1.60 (t, 2H), 1.31 (m, 4H), 1.17 (dq, 1H), 1.11 (dd, 1H), 1.03 (d, 2H), 0.43 (dd, 1H), 0.27 (q, 1H)；LC/MSm/z (M+H) = 448.3。 Instance 5 : N - methyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

Similar to Example 4 self-preparation 46 (100 mg) and 72 mg (±)-2-(tetrahydro-2H -Pyran-4-yl)propionic acid to prepare Example 5 and by preparative HPLC (Phenomenex Gemini-NX C18 150 mm × 30 mm × 5 µM, water (0.04% NH₄ OH)/MeCN, 26% to 66% in 9 min, 25 ml/min) purified to obtainTitle compound (63 mg, 51%). SFC method: Chiral Tech OD-3 100 mm × 4.6 mm × 3 µm, CO₂ /EtOH (0.05%), 5% to 40%, 2.8 mL/min, column temperature: 35℃, retention time = 3.39 min (15.8%), 3.46 min (26.0%), 3.54 min (35.6%) and 3.76 min (22.43%);¹ H NMR (400 MHz, CD₃ OD) δ 7.57 (d, 1H), 7.47 (d, 1H), 4.00-3.80 (m, 2H), 3.47-3.35 (m, 4H), 3.29-3.22 (m, 3H), 3.15 (dd, 1H) , 3.08 (d, 1H), 2.79 (d, 1H), 2.38 (d, 3H), 2.16 (dd, 0.5H), 1.99 (t, 0.5H), 1.90-1.69 (m, 1H), 1.60 (t , 2H), 1.31 (m, 4H), 1.17 (dq, 1H), 1.11 (dd, 1H), 1.03 (d, 2H), 0.43 (dd, 1H), 0.27 (q, 1H); LC/MSm/z (M+H) = 448.3.

步驟 1 ： (S)-N- 乙基 -N-(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

使用製備物19 (162 mg, 1.02 mmol)及EDCI (170 mg, 0.89 mmol)處理製備物67 (200 mg, 0.44 mmol)於吡啶(4.43 mL)中之溶液。將混合物攪拌96 h，然後在80℃下再加熱24 h。使用水稀釋混合物並使用EtOAc (2 × 20 mL)萃取混合物。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%，然後MeOH/DCM = 0-10%)純化粗製材料以得到標題化合物 (78 mg, 30%)。LC/MSm/z (M+H)⁺ = 593.5。步驟 2 ： (S)-N - 乙基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

使用Et₃ SiH (80 mg, 0.69 mmol)在0-5℃下處理步驟1之矽基醚(78 mg, 0.132 mmol)於TFA (1.5 mL)中之溶液。在15℃下攪拌2 h之後，去除溶劑且使用Na₂ CO₃ 飽和水溶液使反應液達到鹼性。使用預混合DCM/MeOH (10:1, 8 mL × 3)萃取混合物併合併萃取物。濃縮並藉由製備型HPLC [YMC-Actus Triart Prep C18 150 mm × 30 mm × 5 µM，水(0.05% NH4OH)/MeCN，在10 min內43%至63%，35 ml/min]純化殘餘物以得到標題化合物 (35 mg, 57%)。SFC方法：Chiral Tech AD-3 50 mm × 4.6 mm × 3 µm, CO₂ /EtOH (0.05%)，40%等梯度，4 mL/min，管柱溫度：35℃，滯留時間= 0.45 min (51.01%)及1.39 (48.99%), 100%ee；¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 12.60 (d, 1H), 7.69 - 7.46 (m, 0.75H), 7.41 - 7.33 (m, 1.25H), 4.11 (tq, 1H), 3.51 - 3.42 (m, 2H), 3.11 - 2.94 (m, 5H), 2.74 (d, 1H), 2.46 (s, 2H), 2.35 (s, 3H), 2.22 (d, 2H), 2.12 - 2.04 (m, 1H), 2.02 (s, 1H), 1.25 (s, 3H), 1.13 - 0.91 (m, 7H), 0.37 (dd, 1H), 0.16 (d, 1H)；LC/MSm/z (M+H)⁺ = 463.2。 Instance 6 : (S)- N- Ethyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

step 1 : (S)-N- Ethyl -N-(6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 67 (200 mg, 0.44 mmol) in pyridine (4.43 mL) was treated with Preparation 19 (162 mg, 1.02 mmol) and EDCI (170 mg, 0.89 mmol). The mixture was stirred for 96 h and then heated at 80°C for another 24 h. The mixture was diluted with water and extracted with EtOAc (2×20 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%, then MeOH/DCM = 0-10%) to obtainTitle compound (78 mg, 30%). LC/MSm/z (M+H)⁺ = 593.5.step 2 : (S)- N- Ethyl -N -(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

Use Et₃ A solution of the silyl ether (78 mg, 0.132 mmol) of step 1 in TFA (1.5 mL) was treated with SiH (80 mg, 0.69 mmol) at 0-5°C. After stirring for 2 h at 15°C, the solvent was removed and Na was used₂ CO₃ The saturated aqueous solution makes the reaction liquid alkaline. The mixture was extracted with premixed DCM/MeOH (10:1, 8 mL×3) and the extracts were combined. Concentrate and purify the residue by preparative HPLC [YMC-Actus Triart Prep C18 150 mm × 30 mm × 5 µM, water (0.05% NH4OH)/MeCN, 43% to 63% in 10 min, 35 ml/min] To getTitle compound (35 mg, 57%). SFC method: Chiral Tech AD-3 50 mm × 4.6 mm × 3 µm, CO₂ /EtOH (0.05%), 40% isocratic, 4 mL/min, column temperature: 35℃, retention time = 0.45 min (51.01%) and 1.39 (48.99%), 100%ee;¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 12.60 (d, 1H), 7.69-7.46 (m, 0.75H), 7.41-7.33 (m, 1.25H), 4.11 (tq, 1H), 3.51-3.42 (m, 2H ), 3.11-2.94 (m, 5H), 2.74 (d, 1H), 2.46 (s, 2H), 2.35 (s, 3H), 2.22 (d, 2H), 2.12-2.04 (m, 1H), 2.02 ( s, 1H), 1.25 (s, 3H), 1.13-0.91 (m, 7H), 0.37 (dd, 1H), 0.16 (d, 1H); LC/MSm/z (M+H)⁺ = 463.2.

步驟 1 ： (R)-N - 甲基 -N -(2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-( 四氫 -2H - 吡喃 -4- 基 ) 丙醯胺

在室溫下，向製備物55 (6.9 g, 16.3 mmol)及製備物22 (2.83 g, 17.9 mmol)於吡啶(163 mL)中之溶液中添加EDCI (6.24 g, 32.6 mmol)。將混合物在25℃下攪拌16 h並使用水(150 mL)及鹽水(150 mL)稀釋。使用EtOAc (2 × 300 mL)萃取所得水性混合物並乾燥(Na₂ SO₄ )萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-90%)純化粗製材料以得到標題化合物 (6.9 g, 75%產率)。¹ H NMR (400 MHz, CD₃ OD) δ 7.77 (s, 0.5 H), 7.65 - 7.51 (m, 1H), 7.40 (s, 0.5H), 7.14 (bs, 1H), 5.56 - 5.37 (m, 2H), 3.94 - 3.77 (m, 2H), 3.63 (t, 2H), 3.45 - 3.06 (m, 8H), 2.78 (d, 1H), 2.31 - 2.10 (m, 1H), 1.83 - 1.68 (m, 1H), 1.60 (d, 2H), 1.32 (s, 3H), 1.28 - 1.11 (m, 2H), 1.05 (d, 3H), 0.98-0.87 (m, 3H), 0.45 (dd, 1H), 0.27 (t, 1H), -0.03 (s, 9H)；LC/MSm/z (M+H)⁺ = 564.2。步驟 2 ： (R)-N - 甲基 -N -(2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-( 四氫 -2H - 吡喃 -4- 基 ) 丙醯胺

使用Et₃ SiH (7.12 g, 61.2 mmol)在25℃下處理步驟1之矽基醚(6.9 g, 12.2 mmol)於TFA (122 mL)中之溶液。在攪拌3 h之後，濃縮混合物並使用NaHCO₃ 飽和水溶液達到鹼性。使用EtOAc (2 × 100 mL)萃取所得混合物。乾燥(Na₂ SO₄ )有機萃取物，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE, 10-100%)純化粗製材料。藉由對掌性SFC (CO₂ /MeOH+ 1% NH₄ OH, Daicel OJ, 250 mm × 50 mm × 10 µm)進一步純化所得材料以得到最終產物(3.43 g, 64.6%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.79-7.41 (m, 2H), 7.17 - 7.05 (m, 1H), 3.87 (td, 2H), 3.41-3.28 (m, 6H), 3.20 - 3.00 (m, 2H), 2.78 (d, 1H), 2.22 (dq, 1H), 1.75 (q, 1H), 1.60 (d, 2H), 1.29 (s, 3H), 1.24-1.12 (m, 2H), 1.05 (d, 3H), 1.00-0.88 (m, 1H), 0.42 (dd, 1H), 0.26 (t, 1H).；LC/MSm/z (M+H)⁺ = 434.3；分析型SFC (ChiralCel OJ-H 150 mm × 4.6 mm × 5 µm, CO₂ /EtOH (0.05%DEA)，5%至40%)，滯留時間= 4.91 min (100%)。 Instance 7 : (R)- N- methyl -N -(2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

step 1 : (R)- N- methyl -N -(2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

At room temperature, to a solution of Preparation 55 (6.9 g, 16.3 mmol) and Preparation 22 (2.83 g, 17.9 mmol) in pyridine (163 mL) was added EDCI (6.24 g, 32.6 mmol). The mixture was stirred at 25°C for 16 h and diluted with water (150 mL) and brine (150 mL). The resulting aqueous mixture was extracted with EtOAc (2 × 300 mL) and dried (Na₂ SO₄ ) Extract, filter and concentrate. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-90%) to obtainTitle compound (6.9 g, 75% yield).¹ H NMR (400 MHz, CD₃ OD) δ 7.77 (s, 0.5 H), 7.65-7.51 (m, 1H), 7.40 (s, 0.5H), 7.14 (bs, 1H), 5.56-5.37 (m, 2H), 3.94-3.77 (m, 2H), 3.63 (t, 2H), 3.45-3.06 (m, 8H), 2.78 (d, 1H), 2.31-2.10 (m, 1H), 1.83-1.68 (m, 1H), 1.60 (d, 2H) , 1.32 (s, 3H), 1.28-1.11 (m, 2H), 1.05 (d, 3H), 0.98-0.87 (m, 3H), 0.45 (dd, 1H), 0.27 (t, 1H), -0.03 ( s, 9H); LC/MSm/z (M+H)⁺ = 564.2.step 2 : (R)- N- methyl -N -(2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

Use Et₃ A solution of the silyl ether (6.9 g, 12.2 mmol) of step 1 in TFA (122 mL) was treated with SiH (7.12 g, 61.2 mmol) at 25°C. After stirring for 3 h, the mixture was concentrated and NaHCO was used₃ The saturated aqueous solution becomes alkaline. The resulting mixture was extracted with EtOAc (2×100 mL). Dry (Na₂ SO₄ ) Organic extract, filtered and concentrated. The crude material was purified by chromatography (silica dioxide, EtOAc/PE, 10-100%). With the SFC (CO₂ /MeOH+ 1% NH₄ OH, Daicel OJ, 250 mm × 50 mm × 10 µm) was further purified to obtain the final product (3.43 g, 64.6%).¹ H NMR (400 MHz, CD₃ OD) δ 7.79-7.41 (m, 2H), 7.17-7.05 (m, 1H), 3.87 (td, 2H), 3.41-3.28 (m, 6H), 3.20-3.00 (m, 2H), 2.78 (d, 1H), 2.22 (dq, 1H), 1.75 (q, 1H), 1.60 (d, 2H), 1.29 (s, 3H), 1.24-1.12 (m, 2H), 1.05 (d, 3H), 1.00-0.88 (m, 1H), 0.42 (dd, 1H), 0.26 (t, 1H).; LC/MSm/z (M+H)⁺ = 434.3; Analytical SFC (ChiralCel OJ-H 150 mm × 4.6 mm × 5 µm, CO₂ /EtOH (0.05%DEA), 5% to 40%), residence time = 4.91 min (100%).

類似於實例7自製備物55 (350 mg)及(±)-2-(四氫-2H - 吡喃-4-基)丙酸(131 mg)來製備實例8並藉由製備型HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 µm, H₂ O/MeCN+0.05% NH₄ OH，在10 min內38%-58%)純化以提供標題化合物 (150 mg, 39.4%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.79-7.38 (m, 2H), 7.13 (dd, 1H), 3.87 (t, 2H), 3.41-3.33 (m, 3H), 3.31 (s, 3H), 3.19 - 3.10 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.21 (dq, 1H), 1.84 - 1.68 (m, 1H), 1.60 (d, 2H), 1.29 (s, 3H), 1.27 - 1.10 (m, 2H), 1.05 (d, 3H), 0.95 (qd, 1H), 0.42 (dd, 1H), 0.26 (t, 1H).；LC/MSm/z (M+H)⁺ = 434.3。 Instance 8 : N - methyl -N -(2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

Similar to Example 7 self-preparation 55 (350 mg) and (±)-2-(tetrahydro-2 H- Pyran-4-yl)propionic acid (131 mg) was used to prepare Example 8 and prepared by preparative HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 µm, H₂ O/MeCN+0.05% NH₄ OH, 38%-58% within 10 min) purified to provideTitle compound (150 mg, 39.4%).¹ H NMR (400 MHz, CD₃ OD) δ 7.79-7.38 (m, 2H), 7.13 (dd, 1H), 3.87 (t, 2H), 3.41-3.33 (m, 3H), 3.31 (s, 3H), 3.19-3.10 (m, 1H) , 3.07 (d, 1H), 2.78 (d, 1H), 2.21 (dq, 1H), 1.84-1.68 (m, 1H), 1.60 (d, 2H), 1.29 (s, 3H), 1.27-1.10 (m , 2H), 1.05 (d, 3H), 0.95 (qd, 1H), 0.42 (dd, 1H), 0.26 (t, 1H).; LC/MSm/z (M+H)⁺ = 434.3.

類似於實例7自製備物55 (296 mg)及(S) -2-(四氫-2H - 吡喃-4-基)丙酸(111 mg)來製備實例9並藉由製備型HPLC (YMC-Actus triart C18, 100 × 30 mm × 5µm, H₂ O/MeCN (0.05% NH₄ OH)，在10 min內38%至58%)純化以得到標題化合物 (102 mg)。¹ H NMR (400 MHz, CD₃ OD) δ 7.81-7.34 (m, 2H), 7.11 (dd, 1H), 3.86 (ddd, 2H), 3.41 - 3.31 (m, 3H), 3.31 (s, 3H), 3.13 (dd, 1H), 3.05 (d, 1H), 2.76 (d, 1H), 2.20 (dq, 1H), 1.73 (td, 1H), 1.58 (dd, 2H), 1.28 (s, 3H), 1.25 - 1.10 (m, 2H), 1.03 (d, 3H), 0.93 (qd, 1H), 0.40 (dd, 1H), 0.24 (t, 1H).；對掌性SFC (ChiralCel OJ-H 150 × 4.6 mm × 5 µm, CO₂ /EtOH (0.05%DEA)，5%至40%)，滯留時間=3.60 min。 Instance 9 : (S)- N- methyl -N -(2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

Similar to Example 7 self-prepared product 55 (296 mg) and(S) -2-(Tetrahydro-2 H- Pyran-4-yl)propionic acid (111 mg) was used to prepare Example 9 and prepared by preparative HPLC (YMC-Actus triart C18, 100 × 30 mm × 5µm, H₂ O/MeCN (0.05% NH₄ OH), 38% to 58% within 10 min) purified to obtainTitle compound (102 mg).¹ H NMR (400 MHz, CD₃ OD) δ 7.81-7.34 (m, 2H), 7.11 (dd, 1H), 3.86 (ddd, 2H), 3.41-3.31 (m, 3H), 3.31 (s, 3H), 3.13 (dd, 1H), 3.05 (d, 1H), 2.76 (d, 1H), 2.20 (dq, 1H), 1.73 (td, 1H), 1.58 (dd, 2H), 1.28 (s, 3H), 1.25-1.10 (m, 2H), 1.03 (d, 3H), 0.93 (qd, 1H), 0.40 (dd, 1H), 0.24 (t, 1H).; Opposite SFC (ChiralCel OJ-H 150 × 4.6 mm × 5 µm, CO₂ /EtOH (0.05%DEA), 5% to 40%), residence time = 3.60 min.

類似於實例7自製備物55 (200 mg)及2-(四氫-2H -吡喃-4-基)乙酸(82 mg)來製備實例10並藉由對掌性SFC (Daicel ChiralCel OJ-H (250 mm × 30 mm × 5 µm), CO₂ /EtOH w/ 0.1% NH₄ OH，25%等梯度)純化以得到標題化合物 (71 mg)。¹ H NMR (400 MHz, CD₃ OD) δ 7.75-7.39 (m, 2H), 7.13 (d, 1H), 3.83 (dd, 2H), 3.41 - 3.32 (m, 4H), 3.14 (dd, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.15 - 1.92 (m, 3H), 1.57 (d, 2H), 1.30 (s, 3H), 1.23 - 0.99 (m, 3H), 0.42 (dd, 1H), 0.26 (t, 1H)；LC/MSm/z (M+H)⁺ = 420.3。 Example 10: N - methyl - N - (2 - (( 4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazol-3-yl )-1 H -Benzo [d] imidazol -5- yl )-2-( tetrahydro- 2 H - pyran- 4 -yl ) acetamide

Similar to Example 7, self-preparation 55 (200 mg) and 2-(tetrahydro- 2H -pyran-4-yl)acetic acid (82 mg) were used to prepare Example 10. Purified by H (250 mm × 30 mm × 5 µm), CO ₂ /EtOH w/ 0.1% NH ₄ OH, 25% isocratic) to obtain the title compound (71 mg). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.75-7.39 (m, 2H), 7.13 (d, 1H), 3.83 (dd, 2H), 3.41-3.32 (m, 4H), 3.14 (dd, 1H) , 3.07 (d, 1H), 2.78 (d, 1H), 2.15-1.92 (m, 3H), 1.57 (d, 2H), 1.30 (s, 3H), 1.23-0.99 (m, 3H), 0.42 (dd , 1H), 0.26 (t, 1H); LC/MS m/z (M+H) ⁺ = 420.3.

類似於實例7自製備物55 (200 mg)及2,2-二氟-2-(四氫-2H -吡喃-4-基)乙酸(170 mg)來製備實例11並藉由對掌性SFC (Daicel ChiralCel OJ-H, 250 mm × 30 mm × 5 µm；CO₂ /EtOH (0.1% NH₄ OH)，25%等梯度)純化以得到標題化合物 (60 mg)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 12.73 (d, 1H), 7.62 (d, 0.5H), 7.55 (d, 0.5H), 7.42 (d, 0.5H), 7.31 (s, 0.5H), 7.13 - 7.04 (m, 1H), 3.87 - 3.74 (m, 2H), 3.47-3.31 (m, 2H), 3.25 (s, 3H), 3.18 (t, 2H), 3.04 - 2.92 (m, 2H), 2.72 (d, 1H), 2.35 - 2.14 (m, 1H), 1.49 (d, 2H), 1.31-1.19 (m, 5H), 1.15 - 1.00 (m, 1H), 0.36 (dd, 1H), 0.14 (t, 1H).；LC/MSm/z (M+H)⁺ = 582.3。 Instance 11 : 2,2- Difluoro -N- methyl -N -(2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

Similar to Example 7 self-preparation 55 (200 mg) and 2,2-difluoro-2-(tetrahydro-2H -Pyran-4-yl)acetic acid (170 mg) was used to prepare Example 11 and used a palm-like SFC (Daicel ChiralCel OJ-H, 250 mm × 30 mm × 5 µm; CO₂ /EtOH (0.1% NH₄ OH), 25% isocratic) purification to obtainTitle compound (60 mg).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 12.73 (d, 1H), 7.62 (d, 0.5H), 7.55 (d, 0.5H), 7.42 (d, 0.5H), 7.31 (s, 0.5H), 7.13- 7.04 (m, 1H), 3.87-3.74 (m, 2H), 3.47-3.31 (m, 2H), 3.25 (s, 3H), 3.18 (t, 2H), 3.04-2.92 (m, 2H), 2.72 ( d, 1H), 2.35-2.14 (m, 1H), 1.49 (d, 2H), 1.31-1.19 (m, 5H), 1.15-1.00 (m, 1H), 0.36 (dd, 1H), 0.14 (t, 1H).; LC/MSm/z (M+H)⁺ = 582.3.

步驟 1 ： (R)-N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-( 四氫 -2H - 吡喃 -4- 基 ) 丙醯胺

在25℃下，向製備物57 (3.0 g, 6.79 mmol)於吡啶(67.9 mL)中之溶液中添加製備物22 (1.50 g, 9.51 mmol)及EDCI (2.87 g, 14.9 mmol)。將混合物在25℃下攪拌16 h並濃縮。使用水稀釋殘餘物並使用EtOAc (5 × 100 mL)萃取。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化粗製材料以得到標題化合物 (2.3 g, 58.2%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.26 (bs, 1H), 6.97 (d,J = 10.9 Hz, 1H), 5.59 - 5.37 (m, 2H), 3.89 (td,J = 12.4, 11.9, 4.1 Hz, 2H), 3.63 (t,J = 7.9 Hz, 2H), 3.49 - 3.30 (m, 6H), 3.25 - 3.09 (m, 2H), 2.78 (d,J = 16.3 Hz, 1H), 2.24 (dq,J = 9.2, 6.7 Hz, 1H), 1.84 - 1.67 (m, 1H), 1.61 (d,J = 13.2 Hz, 2H), 1.36 - 1.13 (m, 6H), 1.07 (d,J = 6.8 Hz, 3H), 0.94 - 0.85 (m, 2H), 0.45 (dd,J = 8.9, 4.6 Hz, 1H), 0.27 (t,J = 5.1 Hz, 1H), -0.02 (s, 9H)；LC/MSm/z (M+H)⁺ = 582.3。步驟 2 ： (R)-N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-( 四氫 -2H - 吡喃 -4- 基 ) 丙醯胺

使用Et₃ SiH (2.30 g, 19.8 mmol)在5℃下處理步驟1之矽基醚(2.30 g, 3.95 mmol)於TFA (39.5 mL)中之溶液。在室溫下攪拌3 h之後，濃縮混合物並使用Na₂ CO₃ 飽和水溶液稀釋殘餘物。使用EtOAc (2 × 30 mL)萃取混合物併合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 20-100%)純化粗製材料。將化合物溶解於MeCN (10 mL)、EtOH (10 mL)及H₂ O (150 mL)中並凍乾以得到標題化合物 (1.78 g, 99%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.25 (s, 1H), 6.95 (d, 1H), 3.95 - 3.78 (m, 2H), 3.43 - 3.25 (m, 6H), 3.20 - 3.11 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.30 - 2.12 (m, 1H), 1.75 (q, 1H), 1.60 (t, 2H), 1.30 (s, 3H), 1.25 - 1.11 (m, 2H), 1.06 (d, 3H), 0.98 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1H).；LC/MSm/z (M+H) = 452.3。 Instance 12 : (R)- N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

step 1 : (R)- N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

At 25°C, to a solution of Preparation 57 (3.0 g, 6.79 mmol) in pyridine (67.9 mL) was added Preparation 22 (1.50 g, 9.51 mmol) and EDCI (2.87 g, 14.9 mmol). The mixture was stirred at 25°C for 16 h and concentrated. The residue was diluted with water and extracted with EtOAc (5×100 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-50%) to obtainTitle compound (2.3 g, 58.2%).¹ H NMR (400 MHz, CD₃ OD) δ 7.26 (bs, 1H), 6.97 (d,J = 10.9 Hz, 1H), 5.59-5.37 (m, 2H), 3.89 (td,J = 12.4, 11.9, 4.1 Hz, 2H), 3.63 (t,J = 7.9 Hz, 2H), 3.49-3.30 (m, 6H), 3.25-3.09 (m, 2H), 2.78 (d,J = 16.3 Hz, 1H), 2.24 (dq,J = 9.2, 6.7 Hz, 1H), 1.84-1.67 (m, 1H), 1.61 (d,J = 13.2 Hz, 2H), 1.36-1.13 (m, 6H), 1.07 (d,J = 6.8 Hz, 3H), 0.94-0.85 (m, 2H), 0.45 (dd,J = 8.9, 4.6 Hz, 1H), 0.27 (t,J = 5.1 Hz, 1H), -0.02 (s, 9H); LC/MSm/z (M+H)⁺ = 582.3.step 2 : (R)- N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2-( Tetrahydro -2 H- Pyran -4- base ) Acetamide

Use Et₃ A solution of the silyl ether (2.30 g, 3.95 mmol) of step 1 in TFA (39.5 mL) was treated with SiH (2.30 g, 19.8 mmol) at 5°C. After stirring for 3 h at room temperature, the mixture was concentrated and Na₂ CO₃ The residue was diluted with saturated aqueous solution. The mixture was extracted with EtOAc (2 × 30 mL) and the organic extracts were combined and dried (Na₂ SO₄ ), filtered and concentrated. The crude material was purified by chromatography (silica dioxide, EtOAc/PE = 20-100%). Dissolve the compound in MeCN (10 mL), EtOH (10 mL) and H₂ O (150 mL) and lyophilize to obtainTitle compound (1.78 g, 99%).¹ H NMR (400 MHz, CD₃ OD) δ 7.25 (s, 1H), 6.95 (d, 1H), 3.95-3.78 (m, 2H), 3.43-3.25 (m, 6H), 3.20-3.11 (m, 1H), 3.07 (d, 1H) , 2.78 (d, 1H), 2.30-2.12 (m, 1H), 1.75 (q, 1H), 1.60 (t, 2H), 1.30 (s, 3H), 1.25-1.11 (m, 2H), 1.06 (d , 3H), 0.98 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1H).; LC/MSm/z (M+H) = 452.3.

步驟 1 ： (4aS,5aR)-N -(2- 胺基 -5-((S)-N - 甲基 -2-N - 𠰌 啉基丙醯胺基 ) 苯基 )-5,5- 二氟 -5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 甲醯胺

使用HBTU (1.75 g, 4.60 mmol)、DMAP (37.5 mg, 0.31 mmol)、i Pr₂ NEt (1.19 mg, 9.2 mmol)及32 (854 mg, 3.07 mmol)在室溫下處理製備物68 (700 mg, 3.07 mmol)於DMF (40 mL)中之溶液。將混合物在80℃下攪拌16 h並使用NaHCO₃ 飽和水溶液(100 mL)稀釋。使用EtOAc (4 × 100 mL)萃取水溶液併合併有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%，然後EtOAc/EtOH = 3:1)純化粗產物以得到標題化合物 (850 mg, 57%)。LC/MSm/z (M+H)⁺ = 488.9。 步驟 2 ： (S)-N -(2-((4aS,5aR)-5,5- 二氟 -5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺

將步驟1之醯胺(850 mg, 1.74 mmol)及AcOH (50 mL)之混合物在90℃下攪拌16 h並濃縮。使用EtOAc (50 mL)稀釋殘餘物並使用飽和Na₂ CO₃ 洗滌。使用EtOAc (4 × 100 mL)萃取水層。分離有機萃取物並濃縮。藉由製備型HPLC (Xtimiate C-18 150 × 25 mm × 5 µm, H₂ O/CH₃ CN (0.225% FA)，在8 min內20 - 40%)純化殘餘物以得到標題化合物 (289 mg, 35%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.75-7.49 (m, 2H), 7.18 (d, 1H), 3.70 - 3.56 (m, 4H), 3.33 (s, 3H), 3.23 (q, 1H), 3.14 (d, 1H), 2.86 (dd, 1H), 2.56 (dt, 2H), 2.40 (dd, 2H), 1.83 - 1.67 (m, 1H), 1.43 (d, 3H), 1.18 (d, 3H)；LC/MSm/z (M+H)⁺ = 435.3。 Instance 13 : (S)- N -(2-((4aS,5aR)-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

step 1 : (4aS,5aR)- N -(2- Amino -5-((S)- N- methyl -2- N- 𠰌 Hydroxypropanamido ) Phenyl )-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- Formamide

Use HBTU (1.75 g, 4.60 mmol), DMAP (37.5 mg, 0.31 mmol),i Pr₂ NEt (1.19 mg, 9.2 mmol) and 32 (854 mg, 3.07 mmol) were treated with a solution of preparation 68 (700 mg, 3.07 mmol) in DMF (40 mL) at room temperature. The mixture was stirred at 80°C for 16 h and NaHCO was used₃ Dilute with saturated aqueous solution (100 mL). The aqueous solution was extracted with EtOAc (4 × 100 mL) and the organic layers were combined and dried (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%, then EtOAc/EtOH = 3:1) to obtainTitle compound (850 mg, 57%). LC/MSm/z (M+H)⁺ = 488.9. step 2 : (S)- N -(2-((4aS,5aR)-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

The mixture of amide (850 mg, 1.74 mmol) and AcOH (50 mL) from step 1 was stirred at 90°C for 16 h and concentrated. Use EtOAc (50 mL) to dilute the residue and use saturated Na₂ CO₃ washing. The aqueous layer was extracted with EtOAc (4×100 mL). The organic extract was separated and concentrated. By preparative HPLC (Xtimiate C-18 150 × 25 mm × 5 µm, H₂ O/CH₃ CN (0.225% FA), 20-40% within 8 min) Purify the residue to obtainTitle compound (289 mg, 35%).¹ H NMR (400 MHz, CD₃ OD) δ 7.75-7.49 (m, 2H), 7.18 (d, 1H), 3.70-3.56 (m, 4H), 3.33 (s, 3H), 3.23 (q, 1H), 3.14 (d, 1H), 2.86 (dd, 1H), 2.56 (dt, 2H), 2.40 (dd, 2H), 1.83-1.67 (m, 1H), 1.43 (d, 3H), 1.18 (d, 3H); LC/MSm/z (M+H)⁺ = 435.3.

步驟 1 ： (S)-N - 甲基 -N -(2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

使用Na₂ S₂ O₃ (1.14 g, 11.0 mml)處理製備物32 (1.53 g, 5.5 mmol)、製備物9 (1.69 g, 5.5 mmol)於EtOH (27.5 mL)及水(2.75 mL)中之混合物。將混合物在90℃下加熱2 h。濃縮混合物並使用EtOAc及H₂ O稀釋殘餘物。分離各層並使用EtOAc (2 ×)萃取水層。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/庚烷= 10-100%，然後EtOAc/MeOH = 0-15%)純化粗產物以得到標題化合物 (2.41 g, 78%)。LC/MSm/z (M+H)⁺ = 565.5。步驟 2 ： (S)-N - 甲基 -N -(2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

使用TFA (8.61 mL)在0℃下處理步驟1之矽基醚(2.41 g, 4.26 mmol)於DCM (12.8 mL)中之溶液並在室溫下攪拌18 h。濃縮混合物並將殘餘物溶於THF/MeOH中，且使用固體K₂ CO₃ 將pH調節至約10。在10%MeOH/DCM中稀釋混合物並使用鹽水洗滌。使用10% MeOH/DCM萃取水層。合併有機萃取物，乾燥，過濾並濃縮。藉由對掌性SFC (ChiralCel OJ, 30 mm × 250 mm × 5 µm, CO₂ /MeOH (0.2% NH₃ )，在10 min內25%等梯度)純化粗產物以得到標題化合物 (0.89 g, 48%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.93 - 12.87 (m, 1H), 12.73 (d,J = 5.9 Hz, 1H), 7.63 (d,J = 8.4 Hz, 0.5H), 7.55 (s, 0.5H), 7.44 (d,J = 8.3 Hz, 0.5H), 7.35 (s, 0.5H), 7.07 (t,J = 9.9 Hz, 1H), 3.50 - 3.41 (m, 5H),3.23-3.13 (m, 4H), 2.98 (dd,J = 16.2, 8.6 Hz, 2H), 2.72 (d,J = 16.1 Hz, 1H), 2.46 - 2.35 (m, 2H), 2.31 - 2.11 (m, 2H), 1.23 (s, 3H), 1.15 - 0.88 (m, 4H), 0.36 (dd,J = 8.8, 4.3 Hz, 1H), 0.14 (s, 1H).；LC/MSm/z (M+H)⁺ = 435.3.；對掌性SFC (Lux Cellulose-2, 150 × 4.6 mm × 3 µm, CO₂ /EtOH (0.1%乙醇胺，1%至40% EtOH)；滯留時間= 2.96 min Instance 14 : (S)- N- methyl -N -(2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

step 1 : (S)- N- methyl -N -(2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

Use Na₂ S₂ O₃ (1.14 g, 11.0 mml) was treated with a mixture of Preparation 32 (1.53 g, 5.5 mmol), Preparation 9 (1.69 g, 5.5 mmol) in EtOH (27.5 mL) and water (2.75 mL). The mixture was heated at 90°C for 2 h. Concentrate the mixture and use EtOAc and H₂ O dilute the residue. The layers were separated and the aqueous layer was extracted with EtOAc (2×). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/heptane = 10-100%, then EtOAc/MeOH = 0-15%) to obtainTitle compound (2.41 g, 78%). LC/MSm/z (M+H)⁺ = 565.5.step 2 : (S)- N- methyl -N -(2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

A solution of step 1 silyl ether (2.41 g, 4.26 mmol) in DCM (12.8 mL) was treated with TFA (8.61 mL) at 0°C and stirred at room temperature for 18 h. The mixture was concentrated and the residue was dissolved in THF/MeOH, and solid K was used₂ CO₃ Adjust the pH to about 10. The mixture was diluted in 10% MeOH/DCM and washed with brine. The aqueous layer was extracted with 10% MeOH/DCM. The organic extracts are combined, dried, filtered, and concentrated. With the SFC (ChiralCel OJ, 30 mm × 250 mm × 5 µm, CO₂ /MeOH (0.2% NH₃ ), 25% isocratic within 10 min) purify the crude product to obtainTitle compound (0.89 g, 48%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.93-12.87 (m, 1H), 12.73 (d,J = 5.9 Hz, 1H), 7.63 (d,J = 8.4 Hz, 0.5H), 7.55 (s, 0.5H), 7.44 (d,J = 8.3 Hz, 0.5H), 7.35 (s, 0.5H), 7.07 (t,J = 9.9 Hz, 1H), 3.50-3.41 (m, 5H), 3.23-3.13 (m, 4H), 2.98 (dd,J = 16.2, 8.6 Hz, 2H), 2.72 (d,J = 16.1 Hz, 1H), 2.46-2.35 (m, 2H), 2.31-2.11 (m, 2H), 1.23 (s, 3H), 1.15-0.88 (m, 4H), 0.36 (dd,J = 8.8, 4.3 Hz, 1H), 0.14 (s, 1H).; LC/MSm/z (M+H)⁺ = 435.3.; Opposite SFC (Lux Cellulose-2, 150 × 4.6 mm × 3 µm, CO₂ /EtOH (0.1% ethanolamine, 1% to 40% EtOH); retention time = 2.96 min

步驟 1 ： (S)-N -(4- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -6- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺及 (S)-N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺

使用19 (45.6 mg, 0.23 mmol)及EDCI (74.4 mg, 0.39 mmol)在15℃下處理於吡啶(2.77 mL)中之製備物74a及74b之混合物(mg, 0.19 mmol)。將混合物攪拌16 h。使用水稀釋混合物並使用EtOAc (2 × 20 mL)萃取。合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 之混合物(131 mg, 95%)。LC/MSm/z (M+Na)⁺ = 735.1步驟 2 ： (S)-N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺

使用Et₃ SIH (107 mg, 0.92 mmol)在10℃下處理步驟1之矽基醚(131 mg, 0.18 mmol)於TFA (1.84 mL)中之混合物。在攪拌3 h之後，濃縮混合物並使用Na₂ CO₃ 飽和水溶液使殘餘物達到鹼性。使用EtOAc (3 × 15 mL)萃取混合物併合併萃取物。去除溶劑且藉由製備型HPLC (H₂ O: MeCN, 0.05% TFA)純化殘餘物以得到標題化合物 (37 mg, 45%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.34 (s, 1H), 7.04 (d, 1H), 4.61 (s, 1H), 3.62 (ddd, 4H), 3.30 (s, 3H), 3.37 (d, 1H), 3.23 (q, 1H), 3.19 - 3.10 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.54 (dt, 2H), 2.36 (dt, 2H), 1.30 (s, 3H), 1.17 (d, 3H), 0.42 (dd, 1H), 0.25 (t, 1H)；LC/MSm/z (M+H)⁺ = 453.3 Instance 15 : (S)- N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

step 1 : (S)- N -(4- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )- N- methyl -2- N- 𠰌 Linylpropanamide and (S)- N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

A mixture of preparations 74a and 74b (mg, 0.19 mmol) in pyridine (2.77 mL) was treated with 19 (45.6 mg, 0.23 mmol) and EDCI (74.4 mg, 0.39 mmol) at 15°C. The mixture was stirred for 16 h. The mixture was diluted with water and extracted with EtOAc (2×20 mL). Combine the organic extracts and dry (Na₂ SO₄ ), filtered and concentrated to getTitle compound The mixture (131 mg, 95%). LC/MSm/z (M+Na)⁺ = 735.1step 2 : (S)- N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use Et₃ The mixture of silyl ether (131 mg, 0.18 mmol) in TFA (1.84 mL) from step 1 was treated with SIH (107 mg, 0.92 mmol) at 10°C. After stirring for 3 h, the mixture was concentrated and Na₂ CO₃ The saturated aqueous solution makes the residue alkaline. The mixture was extracted with EtOAc (3×15 mL) and the extracts were combined. Remove the solvent and by preparative HPLC (H₂ O: MeCN, 0.05% TFA) the residue was purified to obtainTitle compound (37 mg, 45%).¹ H NMR (400 MHz, CD₃ OD) δ 7.34 (s, 1H), 7.04 (d, 1H), 4.61 (s, 1H), 3.62 (ddd, 4H), 3.30 (s, 3H), 3.37 (d, 1H), 3.23 (q, 1H) ), 3.19-3.10 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.54 (dt, 2H), 2.36 (dt, 2H), 1.30 (s, 3H), 1.17 (d, 3H), 0.42 (dd, 1H), 0.25 (t, 1H); LC/MSm/z (M+H)⁺ = 453.3

步驟 1 ： (S)-N - 乙基 -N -(4- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -6- 基 )-2-N - 𠰌 啉基丙醯胺及 (S)-N - 乙基 -N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

使用EDCI (4.02 g, 21.0 mmol)在30℃下處理製備物76a及76b (6.14 g, 10.48 mmol)及19 (1.46 g, 9.17 mmol)於吡啶(70 mL)中之混合物。在攪拌16 h之後，去除溶劑且添加水(80 mL)。使用EtOAc (2 × 80 mL)萃取混合物併合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-50%)純化粗產物以得到標題化合物 之混合物(5.13 g, 67%)。LC/MSm/z (M+H) = 727.4步驟 2 ： (S)-N - 乙基 -N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

使用Et₃ SiH (4.1 g, 35.3 mmol)在0℃下處理步驟1之矽基醚(5.13 g, 7.06 mmol)於TFA (35 mL)中之混合物。將混合物在30℃下攪拌3 h。濃縮混合物並使用NaHCO₃ 飽和水溶液稀釋殘餘物。使用EtOAc (2 × 100 mL)萃取混合物併合併有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮。對粗產物實施層析(二氧化矽，EtOAc/PE = 0-50%。(2.66 g, 81%)。藉由對掌性SFC (DaicelChiralpak AD, 250 mm × 50 mm × 10 µm；CO₂ /EtOH(0.1%NH₄ OH), 50%等梯度)進一步純化混合物以得到標題化合物 (1.72 g, 52%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.31 (bs, 1H), 7.05 - 6.93 (m, 1H), 3.78 (s, 2H), 3.61 (ddd, 4H), 3.38 (d, 1H), 3.14 (dt, 2H), 3.06 (d, 1H), 2.76 (d, 1H), 2.53 (dt, 2H), 2.35 (dt, 2H), 1.28 (s, 3H), 1.20 - 1.11 (m, 7H), 0.40 (dd, 1H), 0.24 (t, 1H)；LC/MSm/z (M+H)⁺ = 467.1。 Instance 16 : (S)-N- Ethyl -N-(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

step 1 : (S)- N- Ethyl -N -(4- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )-2- N- 𠰌 Linylpropanamide and (S)- N- Ethyl -N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

A mixture of preparations 76a and 76b (6.14 g, 10.48 mmol) and 19 (1.46 g, 9.17 mmol) in pyridine (70 mL) was treated with EDCI (4.02 g, 21.0 mmol) at 30°C. After stirring for 16 h, the solvent was removed and water (80 mL) was added. The mixture was extracted with EtOAc (2 × 80 mL) and the organic extracts were combined and dried (Na₂ SO₄ ), filtered and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-50%) to obtainTitle compound The mixture (5.13 g, 67%). LC/MSm/z (M+H) = 727.4step 2 : (S)- N- Ethyl -N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

Use Et₃ A mixture of the silyl ether (5.13 g, 7.06 mmol) of step 1 in TFA (35 mL) was treated with SiH (4.1 g, 35.3 mmol) at 0°C. The mixture was stirred at 30°C for 3 h. Concentrate the mixture and use NaHCO₃ The residue was diluted with saturated aqueous solution. The mixture was extracted with EtOAc (2 × 100 mL) and the organic extracts were combined and dried (Na₂ SO₄ ), filtered and concentrated. The crude product was chromatographed (silica dioxide, EtOAc/PE = 0-50%. (2.66 g, 81%). By contrast SFC (DaicelChiralpak AD, 250 mm × 50 mm × 10 µm; CO)₂ /EtOH(0.1%NH₄ OH), 50% isocratic) further purify the mixture to obtainTitle compound (1.72 g, 52%).¹ H NMR (400 MHz, CD₃ OD) δ 7.31 (bs, 1H), 7.05-6.93 (m, 1H), 3.78 (s, 2H), 3.61 (ddd, 4H), 3.38 (d, 1H), 3.14 (dt, 2H), 3.06 (d , 1H), 2.76 (d, 1H), 2.53 (dt, 2H), 2.35 (dt, 2H), 1.28 (s, 3H), 1.20-1.11 (m, 7H), 0.40 (dd, 1H), 0.24 ( t, 1H); LC/MSm/z (M+H)⁺ = 467.1.

步驟 1 ： (S)-N -(6- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺及 (S)-N -(5- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -6- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺

使用19 (71 mg, 0.45 mmol)及EDCI (114 mg, 0.6 mmol)在15℃下處理於吡啶(4.95 mL)中之製備物80a及80b之混合物(170 mg, 0.29 mmol)。將混合物攪拌2天，然後使用水稀釋並使用EtOAc (2 × 20 mL)萃取。收集有機萃取物，乾燥(Na₂ SO₄ )，過濾並濃縮以得到標題化合物 之混合物(180 mg, 85%)。LC/MSm/z (M+H)⁺ = 713.5步驟 2 ： (S)-N -(6- 氟 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺

使用Et₃ SiH (147 mg, 1.26 mmol)在10℃下處理步驟1之矽基醚(180 mg, 0.25 mmol)於TFA (2.52 mL)中之混合物。將混合物攪拌3 h並濃縮。使用Na₂ CO₃ 飽和水溶液使混合物達到鹼性並使用EtOAc (3 × 8 mL)萃取。濃縮合併之萃取物且藉由製備型HPLC (YMC-Triart Prep C18 150 mm × 40 mm × 7 µM，水(0.05% NH₄ OH)/MeCN，在10 min內42%至62%，25 ml/min)純化殘餘物以得到標題化合物 (38 mg, 34%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.72 - 7.39 (m, 2H), 3.69 - 3.50 (m, 4H), 3.39 (d, 1H), 3.30 (d, 3H), 3.27 - 3.04 (m, 3H), 2.79 (d, 1H), 2.54 (dt, 1H), 2.41 (dd, 2H), 2.27 (ddd, 1H), 1.31 (s, 3H), 1.23 - 1.12 (m, 4H), 0.44 (dd, 1H), 0.27 (t, 1H)；LC/MSm/z (M+H)⁺ = 453.2。 Instance 17 : (S)- N -(6- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

step 1 : (S)- N -(6- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Linylpropanamide and (S)- N -(5- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

A mixture of preparations 80a and 80b (170 mg, 0.29 mmol) in pyridine (4.95 mL) was treated with 19 (71 mg, 0.45 mmol) and EDCI (114 mg, 0.6 mmol) at 15°C. The mixture was stirred for 2 days, then diluted with water and extracted with EtOAc (2×20 mL). Collect organic extracts and dry (Na₂ SO₄ ), filtered and concentrated to getTitle compound The mixture (180 mg, 85%). LC/MSm/z (M+H)⁺ = 713.5step 2 : (S)- N -(6- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use Et₃ SiH (147 mg, 1.26 mmol) was used to treat a mixture of the silyl ether (180 mg, 0.25 mmol) of step 1 in TFA (2.52 mL) at 10°C. The mixture was stirred for 3 h and concentrated. Use Na₂ CO₃ Saturated aqueous solution made the mixture basic and extracted with EtOAc (3×8 mL). The combined extracts were concentrated and subjected to preparative HPLC (YMC-Triart Prep C18 150 mm × 40 mm × 7 µM, water (0.05% NH₄ OH)/MeCN, 42% to 62% in 10 min, 25 ml/min) purify the residue to obtainTitle compound (38 mg, 34%).¹ H NMR (400 MHz, CD₃ OD) δ 7.72-7.39 (m, 2H), 3.69-3.50 (m, 4H), 3.39 (d, 1H), 3.30 (d, 3H), 3.27-3.04 (m, 3H), 2.79 (d, 1H) , 2.54 (dt, 1H), 2.41 (dd, 2H), 2.27 (ddd, 1H), 1.31 (s, 3H), 1.23-1.12 (m, 4H), 0.44 (dd, 1H), 0.27 (t, 1H) ); LC/MSm/z (M+H)⁺ = 453.2.

類似於實例1自5-氯-2-乙基-4-硝基苯胺來製備實例18以提供標題化合物 (50 mg, 57%)。1H NMR (400 MHz, CD₃ OD) δ 7.54 (s, 2H), 3.69 - 3.58 (m, 4H), 3.38 (d, 1H), 3.27 (d, 3H), 3.20 - 3.01 (m, 3H), 2.87 - 2.72 (m, 1H), 2.67 (q, 2H), 2.56 (d, 2H), 2.35 - 2.27 (m, 2H), 1.37 (dt, 3H), 1.31 (s, 3H), 1.19 (t, 2H), 1.11 (dd, J = 6.6, 1.7 Hz, 2H), 0.44 (dd, 1H), 0.28 (d, J = 5.6 Hz, 1H).；LC/MSm/z (M+H)⁺ = 463.4。 Instance 18 : (S)- N -(6- Ethyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Similar to Example 1, Example 18 was prepared from 5-chloro-2-ethyl-4-nitroaniline to provideTitle compound (50 mg, 57%). 1H NMR (400 MHz, CD₃ OD) δ 7.54 (s, 2H), 3.69-3.58 (m, 4H), 3.38 (d, 1H), 3.27 (d, 3H), 3.20-3.01 (m, 3H), 2.87-2.72 (m, 1H) , 2.67 (q, 2H), 2.56 (d, 2H), 2.35-2.27 (m, 2H), 1.37 (dt, 3H), 1.31 (s, 3H), 1.19 (t, 2H), 1.11 (dd, J = 6.6, 1.7 Hz, 2H), 0.44 (dd, 1H), 0.28 (d, J = 5.6 Hz, 1H).; LC/MSm/z (M+H)⁺ = 463.4.

步驟 1 ： (S)-N -(6- 甲氧基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺

使用製備物9 (157 mg, 0.51mmol)處理製備物84 (189 mg, 0.61 mmol)、Na₂ S₂ O₅ (126 mg, 0.66 mmol)於DMF (7.3 mL)中之混合物。將混合物於微波反應器中在150℃下加熱2 h並傾倒至3% LiCl水溶液(20 mL)及EtOAc (30 mL)中。分離各層並使用EtOAc (30 mL)萃取水層。收集有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。對粗產物實施層析(二氧化矽，EtOAc/PE = 0-100%)以得到標題化合物 (201 mg, 44%)。LC/MSm/z (M+H)⁺ = 595.3。步驟 2 ： (S)-N -(6- 甲氧基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺

使用Et₃ SiH (196 mg, 1.69 mmol)在0-5℃下處理步驟1之矽基醚(201 mg, 0.338 mmol)於TFA (3.38 mL)中之溶液。將混合物在室溫下攪拌2 h並濃縮。使用NaHCO₃ 飽和水溶液使殘餘物達到鹼性。使用EtOAc (2 × 20 mL)萃取混合物並濃縮萃取物。藉由製備型HPLC (YMC Triart C18 150 mm × 30 mm × 7 µM，水(0.05% NH₄ OH)/MeCN，在10 min內25%至75%，25 ml/min)純化殘餘物以得到標題化合物 (87 mg, 55%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.56 (s, 1H), 7.28 (s, 1H), 3.94 (d, 3H), 3.63 (tq, 4H), 3.41 - 3.34 (m, 1H), 3.23 (d, 3H), 3.20 - 3.08 (m, 2H), 3.08 - 2.97 (m, 1H), 2.79 (d, 1H), 2.54 (dt, 1H), 2.44 (dt, 3H), 1.31 (s, 3H), 1.26 - 1.10 (m, 4H), 0.43 (dd, 1H), 0.27 (t, 1H)；LC/MSm/z (M+H)⁺ = 465.2。 Instance 19 : (S)- N -(6- Methoxy -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

step 1 : (S)- N -(6- Methoxy -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use preparation 9 (157 mg, 0.51 mmol) to treat preparation 84 (189 mg, 0.61 mmol), Na₂ S₂ O₅ (126 mg, 0.66 mmol) in DMF (7.3 mL). The mixture was heated in a microwave reactor at 150°C for 2 h and poured into 3% aqueous LiCl (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (30 mL). Collect the organic layer and dry (Na₂ SO₄ ), filtered and concentrated. The crude product was subjected to chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (201 mg, 44%). LC/MSm/z (M+H)⁺ = 595.3.step 2 : (S)- N -(6- Methoxy -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use Et₃ A solution of the silyl ether (201 mg, 0.338 mmol) of step 1 in TFA (3.38 mL) was treated with SiH (196 mg, 1.69 mmol) at 0-5°C. The mixture was stirred at room temperature for 2 h and concentrated. Use NaHCO₃ The saturated aqueous solution makes the residue alkaline. The mixture was extracted with EtOAc (2×20 mL) and the extract was concentrated. By preparative HPLC (YMC Triart C18 150 mm × 30 mm × 7 µM, water (0.05% NH₄ OH)/MeCN, 25% to 75% in 10 min, 25 ml/min) purify the residue to obtainTitle compound (87 mg, 55%).¹ H NMR (400 MHz, CD₃ OD) δ 7.56 (s, 1H), 7.28 (s, 1H), 3.94 (d, 3H), 3.63 (tq, 4H), 3.41-3.34 (m, 1H), 3.23 (d, 3H), 3.20-3.08 (m, 2H), 3.08-2.97 (m, 1H), 2.79 (d, 1H), 2.54 (dt, 1H), 2.44 (dt, 3H), 1.31 (s, 3H), 1.26-1.10 (m, 4H ), 0.43 (dd, 1H), 0.27 (t, 1H); LC/MSm/z (M+H)⁺ = 465.2.

使用Et₃ SiH (90.3 mg, 0.77 mmol)在0℃下處理製備物85 (100 mg, 0.155 mmol)於TFA (5.0 mL)中之溶液。將混合物攪拌2 h並濃縮。將殘餘物溶於MeOH (10 mL)中並使用濃NH₄ OH (1 mL)處理。將混合物在室溫下攪拌1 h並濃縮。藉由製備型HPLC (Boston Prime C18, 150 × 30 mm × 5 µm, H₂ O/MeCN (0.05% NH₄ OH)，在10 min內10 - 70%)純化殘餘物以得到標題化合物 (61 mg, 76%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.09 - 12.65 (m, 2H), 7.99-7.63 (m, 2H), 3.58 - 3.38 (m, 5H), 3.18 - 3.09 (m, 3H), 3.08 - 2.86 (m, 2H), 2.81 - 2.60 (m, 1H), 2.46 - 2.28 (m, 2H), 2.24 - 1.91 (m, 2H), 1.24 (s, 3H), 1.17 - 0.90 (m, 4H), 0.37 (dd, 1H), 0.15 (t, 1H).；LC/MSm/z (M+H)⁺ = 513.3/515.5 (⁷⁹ Br,⁸¹ Br)。 Instance 20 : (S)- N -(6- bromine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use Et₃ A solution of Preparation 85 (100 mg, 0.155 mmol) in TFA (5.0 mL) was treated with SiH (90.3 mg, 0.77 mmol) at 0°C. The mixture was stirred for 2 h and concentrated. Dissolve the residue in MeOH (10 mL) and use concentrated NH₄ OH (1 mL) treatment. The mixture was stirred at room temperature for 1 h and concentrated. By preparative HPLC (Boston Prime C18, 150 × 30 mm × 5 µm, H₂ O/MeCN (0.05% NH₄ OH), within 10 min 10-70%) purify the residue to obtainTitle compound (61 mg, 76%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.09-12.65 (m, 2H), 7.99-7.63 (m, 2H), 3.58-3.38 (m, 5H), 3.18-3.09 (m, 3H), 3.08-2.86 (m, 2H), 2.81-2.60 (m, 1H), 2.46-2.28 (m, 2H), 2.24-1.91 (m, 2H), 1.24 (s, 3H), 1.17-0.90 (m, 4H), 0.37 (dd, 1H), 0.15 (t , 1H).; LC/MSm/z (M+H)⁺ = 513.3/515.5 (⁷⁹ Br,⁸¹ Br).

使用Et₃ SiH (121 mg, 1.04 mmol)在0℃下處理製備物87a及87b (150 mg, 0.21 mmol)於TFA (5 mL)中之混合物。將混合物攪拌2 h並濃縮。將殘餘物溶於MeOH (10 mL)中且添加濃NH₄ OH (1 mL)。將混合物攪拌1 h且濃縮混合物。藉由製備型HPLC (Boston Prime C18, 150 × 30 mm × 5 µm；H₂ O/MeCN (0.2%FA)，在10 min內23-45%)純化殘餘物以得到標題化合物 (34 mg, 35%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.22-13.05 (m, 2H), 8.35 - 7.36 (m, 2H), 3.58 - 3.25 (m, 5H), 3.22 (d, 3H), 3.01 (dd, 2H), 2.80 - 2.56 (m, 2H), 2.44 - 2.27 (m, 2H), 2.12 - 1.90 (m, 2H), 1.25 (s, 3H), 1.18 - 0.95 (m, 34H), 0.38 (dd, 1H), 0.16 (t, 1H)；LC/MSm/z (M+H)⁺ = 460.2。 Instance 21. (S)- N -(6- Cyano -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use Et₃ A mixture of preparations 87a and 87b (150 mg, 0.21 mmol) in TFA (5 mL) was treated with SiH (121 mg, 1.04 mmol) at 0°C. The mixture was stirred for 2 h and concentrated. The residue was dissolved in MeOH (10 mL) and concentrated NH was added₄ OH (1 mL). The mixture was stirred for 1 h and the mixture was concentrated. By preparative HPLC (Boston Prime C18, 150 × 30 mm × 5 µm; H₂ O/MeCN (0.2% FA), 23-45% within 10 min) purify the residue to obtainTitle compound (34 mg, 35%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.22-13.05 (m, 2H), 8.35-7.36 (m, 2H), 3.58-3.25 (m, 5H), 3.22 (d, 3H), 3.01 (dd, 2H), 2.80-2.56 (m, 2H) ), 2.44-2.27 (m, 2H), 2.12-1.90 (m, 2H), 1.25 (s, 3H), 1.18-0.95 (m, 34H), 0.38 (dd, 1H), 0.16 (t, 1H); LC/MSm/z (M+H)⁺ = 460.2.

步驟 1 ： N -(4- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -6- 基 )-N - 甲基 -2-(3- 側氧基 - N - 𠰌 啉基 ) 丙醯胺及 N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-(3- 側氧基 - N - 𠰌 啉基 ) 丙醯胺

使用EDCI (101 mg, 0.53 mmol)在25℃下處理於吡啶(3.75 mL)中之製備物74a及74b之混合物 (150 mg, 0.26 mmol)及製備物26 (54.5 mg, 0.32 mmol)。將混合物攪拌48h並使用水(20 mL)稀釋。使用EtOAc (3 × 20 mL)萃取混合物。合併有機萃取物，乾燥並濃縮以得到標題化合物 之混合物(60 mg, 31%)。LC/MSm/z (M+H)⁺ = 727.3。步驟 2 ： (S)-N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-(3- 側氧基 - N - 𠰌 啉基 ) 丙醯胺及 (R)-N -(7- 氟 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-(3- 側氧基 - N - 𠰌 啉基 ) 丙醯胺

使用Et₃ SiH (68.0 mg, 0.58 mmol)在5℃下處理步驟1之矽基烯醇醚(85.0 mg, 0.12 mmol)於TFA (1.2 mL)中之混合物。將混合物攪拌2 h並濃縮。使用NaHCO₃ 飽和水溶液處理混合物並使用EtOAc (3 × 8 mL)萃取。合併有機萃取物，乾燥，過濾並濃縮，且藉由製備型HPLC (Phenomenex Gemini NX-C18, 75 × 30 mm × 3 µm，MeCN/H₂ O(0.225% FA)，在10 min內29 - 49%)純化殘餘物。藉由對掌性SFC (DaicelChiralpak AD, 250 mm × 30 mm × 10 µm, CO₂ /EtOH(0.1% NH₄ OH), 55%等梯度)分離混合物以得到在任意定義之C-2甲基處具有絕對立體化學之標題化合物 。 實例22：¹ H NMR (400 MHz, CD₃ OD) δ 7.44 - 7.40 (m 1H), 7.08 (d, 1H), 5.14 - 5.07 (m, 1H), 4.03 - 3.85 (m, 3H), 3.81 - 3.71 (m, 1H), 3.56 - 3.44 (m, 1H), 3.38 -3.25 (m, 4H), 3.14 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s, 3H), 1.25 (d, 3H), 1.16 (dt, 1H), 0.41 (dd, 1H), 0.25 (t, 1H)；LC/MSm/z (M+H)⁺ = 467.1。 實例23：¹ H NMR (400 MHz, CD₃ OD) δ 7.42 (s, 1H), 7.08 (d, 1H), 5.13 - 5.08 (m, 1H), 4.00 - 3.86 (m, 3H), 3.82 - 3.70 (m, 1H), 3.56 - 3.45 (m, 1H), 3.39 - 3.24 (m, 4H), 3.14 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s, 3H), 1.25 (d, 3H), 1.16 (dt, 1H), 0.41 (dd, 1H), 0.25 (t, 1H)；LC/MSm/z (M+H)⁺ = 467.1。 Instance twenty two : (S)-N-(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-N- methyl -2-(3- Pendant Oxygen - N - 𠰌 Linyl ) Acetamide ； and Instance twenty three : (R)-N-(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-N- methyl -2-(3- Pendant Oxygen - N - 𠰌 Linyl ) Acetamide

step 1 : N -(4- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -6- base )- N- methyl -2-(3- Pendant Oxygen - N - 𠰌 Linyl ) Acetamide and N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2-(3- Pendant Oxygen - N - 𠰌 Linyl ) Acetamide

A mixture of preparations 74a and 74b (150 mg, 0.26 mmol) and preparation 26 (54.5 mg, 0.32 mmol) in pyridine (3.75 mL) were treated with EDCI (101 mg, 0.53 mmol) at 25°C. The mixture was stirred for 48 h and diluted with water (20 mL). The mixture was extracted with EtOAc (3×20 mL). Combine the organic extracts, dry and concentrate to obtainTitle compound The mixture (60 mg, 31%). LC/MSm/z (M+H)⁺ = 727.3.step 2 : (S)- N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2-(3- Pendant Oxygen - N - 𠰌 Linyl ) Acetamide and (R)- N -(7- fluorine -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2-(3- Pendant Oxygen - N - 𠰌 Linyl ) Acetamide

Use Et₃ SiH (68.0 mg, 0.58 mmol) was treated with a mixture of silyl enol ether (85.0 mg, 0.12 mmol) in TFA (1.2 mL) at 5°C. The mixture was stirred for 2 h and concentrated. Use NaHCO₃ The mixture was treated with saturated aqueous solution and extracted with EtOAc (3×8 mL). The organic extracts were combined, dried, filtered and concentrated, and subjected to preparative HPLC (Phenomenex Gemini NX-C18, 75 × 30 mm × 3 µm, MeCN/H₂ The residue was purified with O (0.225% FA), 29-49% in 10 min. By means of opposing SFC (DaicelChiralpak AD, 250 mm × 30 mm × 10 µm, CO₂ /EtOH(0.1% NH₄ OH), 55% isocratic) to separate the mixture to obtain an absolute stereochemistry at the arbitrarily defined C-2 methyl groupTitle compound . Example 22:¹ H NMR (400 MHz, CD₃ OD) δ 7.44-7.40 (m 1H), 7.08 (d, 1H), 5.14-5.07 (m, 1H), 4.03-3.85 (m, 3H), 3.81-3.71 (m, 1H), 3.56-3.44 (m , 1H), 3.38 -3.25 (m, 4H), 3.14 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s, 3H), 1.25 (d, 3H), 1.16 ( dt, 1H), 0.41 (dd, 1H), 0.25 (t, 1H); LC/MSm/z (M+H)⁺ = 467.1. Example 23:¹ H NMR (400 MHz, CD₃ OD) δ 7.42 (s, 1H), 7.08 (d, 1H), 5.13-5.08 (m, 1H), 4.00-3.86 (m, 3H), 3.82-3.70 (m, 1H), 3.56-3.45 (m, 1H), 3.39-3.24 (m, 4H), 3.14 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s, 3H), 1.25 (d, 3H), 1.16 (dt , 1H), 0.41 (dd, 1H), 0.25 (t, 1H); LC/MSm/z (M+H)⁺ = 467.1.

使用Et₃ SiH (2.60 g, 22.3 mmol)在0℃下處理於TFA (45 mL)中之製備物95a及95b之混合物(3.26 g, 4.47 mmol)。將混合物攪拌5 h並濃縮。使用NaHCO₃ 飽和水溶液處理混合物並使用DCM (3 × 30 mL)萃取。合併有機萃取物，乾燥，過濾並濃縮。對殘餘物實施層析(二氧化矽，MeOH/EtOAc = 0-7%)並將所分離材料溶於MeOH (30 mL)/H₂ O (50 mL)中。藉由凍乾去除溶劑以得到標題化合物 (1.56 g, 69%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.56 - 7.30 (m, 1H), 3.67 - 3.46 (m, 4H), 3.44 - 3.22 (m, 5H), 3.22 - 3.09 (m, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 2.58 - 2.29 (m, 3H), 2.19 (ddd, 1H), 1.29 (s, 3H), 1.15 (dd, 4H), 0.42 (dd, 1H), 0.24 (t, 1H).；¹⁹ F NMR (377 MHz, CD₃ OD) δ -153.83。 Instance twenty four : (S)- N -(6,7- Difluoro -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use Et₃ A mixture of preparations 95a and 95b (3.26 g, 4.47 mmol) in TFA (45 mL) was treated with SiH (2.60 g, 22.3 mmol) at 0°C. The mixture was stirred for 5 h and concentrated. Use NaHCO₃ The mixture was treated with saturated aqueous solution and extracted with DCM (3×30 mL). The organic extracts are combined, dried, filtered, and concentrated. The residue was chromatographed (silica, MeOH/EtOAc=0-7%) and the separated material was dissolved in MeOH (30 mL)/H₂ O (50 mL). Removal of solvent by lyophilization to obtainTitle compound (1.56 g, 69%).¹ H NMR (400 MHz, CD₃ OD) δ 7.56-7.30 (m, 1H), 3.67-3.46 (m, 4H), 3.44-3.22 (m, 5H), 3.22-3.09 (m, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 2.58-2.29 (m, 3H), 2.19 (ddd, 1H), 1.29 (s, 3H), 1.15 (dd, 4H), 0.42 (dd, 1H), 0.24 (t, 1H).;¹⁹ F NMR (377 MHz, CD₃ OD) δ -153.83.

使用Et₃ SiH (93.6 mg, 0.81 mmol)在5℃下處理於TFA (1.6 mL)中之製備物96a及96b之混合物(120 mg, 0.16 mmol)。將混合物攪拌2 h並濃縮。使用NaHCO₃ 飽和水溶液(5 mL)稀釋殘餘物並使用EtOAc (3 × 8 mL)萃取。收集有機萃取物，乾燥，過濾並濃縮。藉由製備型HPLC (YMC Triart, 30 × 150 mm × 7 µm, CH₃ CN/H₂ O (0.05% NH4OH)，在10 min內46-66%)純化殘餘物以得到標題化合物 (7.2 mg, 9%)。¹ H NMR (400 MHz，甲醇-d ₄ ) δ 7.41-7.26 (m,, 1H), 3.90 - 3.66 (m, 1H), 3.65 - 3.46 (m, 4H), 3.44 - 3.32 (m, 1H), 3.23 - 3.10 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.56 - 2.41 (m, 2H), 2.38 - 2.19 (m, 1H), 1.30 (s, 3H), 1.19 - 1.14 (m, 6H), 0.42 (dd, 1H), 0.25 (t, 1H)；LC/MSm/z (M+H)⁺ = 485.1。 Instance 25 : (S)- N -(6.7- Difluoro -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- Ethyl -2- N- 𠰌 Hydroxypropionamide

Use Et₃ A mixture of preparations 96a and 96b (120 mg, 0.16 mmol) in TFA (1.6 mL) was treated with SiH (93.6 mg, 0.81 mmol) at 5°C. The mixture was stirred for 2 h and concentrated. Use NaHCO₃ The residue was diluted with saturated aqueous solution (5 mL) and extracted with EtOAc (3×8 mL). The organic extracts are collected, dried, filtered, and concentrated. By preparative HPLC (YMC Triart, 30 × 150 mm × 7 µm, CH₃ CN/H₂ O (0.05% NH4OH), 46-66% in 10 min) purify the residue to obtainTitle compound (7.2 mg, 9%).¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.41-7.26 (m,, 1H), 3.90-3.66 (m, 1H), 3.65-3.46 (m, 4H), 3.44-3.32 (m, 1H), 3.23-3.10 (m, 1H), 3.07 ( d, 1H), 2.78 (d, 1H), 2.56-2.41 (m, 2H), 2.38-2.19 (m, 1H), 1.30 (s, 3H), 1.19-1.14 (m, 6H), 0.42 (dd, 1H), 0.25 (t, 1H); LC/MSm/z (M+H)⁺ = 485.1.

步驟 1 ： 2-((S)-2-( 羥甲基 ) - N - 𠰌 啉基 )-N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H - 苯并 [d ] 咪唑 -5- 基 ) 乙醯胺

使用NaI (40 mg, 0.27 mmol)及K₂ CO₃ (40 mg, 0.29 mmol)處理製備物98 (130 mg, 0.20 mmol)及(S) -嗎啉-2-基甲醇(26 mg, 0.22 mmol)於MeCN (5 mL)中之溶液。將混合物在80℃下加熱16 h。將混合物冷卻至室溫並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%，然後MeOH/EtOAc = 0-20%)純化殘餘物以得到標題化合物 (108 mg, 74%)。¹ H NMR (400 MHz，氯仿-d) δ 7.71 (s, 1H), 7.36 (d, 1H), 6.22 - 6.07 (m, 1H), 6.09 - 5.93 (m, 1H), 5.42 (q, 2H), 3.94 - 3.73 (m, 4H), 3.71 - 3.37 (m, 8H), 3.26 (s, 3H), 3.19 - 3.01 (m, 2H), 2.96 - 2.68 (m, 4H), 2.34 (s, 4H), 1.38 - 1.27 (m, 3H), 1.17 - 1.01 (m, 2H), 0.91 (t, 2H), 0.87 - 0.73 (m, 2H), 0.40 (s, 1H), 0.26 (d, 1H), -0.02 (s, 9H), -0.11 (t, 9H)；LC/MSm/z (M+H)⁺ = 725.4。步驟 2 ： 2-((S)-2-( 羥甲基 ) - N - 𠰌 啉基 )-N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1H - 苯并 [d ] 咪唑 -5- 基 ) 乙醯胺

使用TFA (1.5 mL)在15℃下處理步驟1之矽基醚(108 mg, 0.149 mmol)於DCM (5 mL)中之溶液。將混合物在15℃下攪拌2 h並濃縮。將殘餘物溶解於MeOH (5 mL)中並使用濃NH₄ OH (2 mL)處理。將混合物在室溫下攪拌2 h。濃縮混合物並藉由製備型HPLC (Welch Xtimate 75 mm × 40 mm × 3 µm，16%至56%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 10 min)純化殘餘物以得到標題化合物 (16 mg, 23%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.68 - 7.39 (m, 2H), 3.77 (d, 1H), 3.72 - 3.52 (m, 2H), 3.52 - 3.40 (m, 2H), 3.40 - 3.33 (m, 2H), 3.24 (s, 3H), 3.19 - 2.93 (m, 3H), 2.86 - 2.59 (m, 4H), 2.35 (s, 3H), 2.19 - 2.04 (m, 1H), 1.85 (dt, 1H), 1.29 (s, 3H), 1.24 - 1.05 (m, 1H), 0.42 (dt, 1H), 0.24 (t, 1H)；LC/MSm/z (M+H)⁺ = 465.3。 藉由實例18中所闡述之程序或其類似程序(藉由採用DIPEA+K₂ CO₃ /NaI)自適當胺及2-氯-N -甲基-N -(6-甲基-2-((4aS ,5aR )-5a-甲基-1-((2-(三甲基矽基)乙氧基)甲基)-1,4,4a,5,5a,6-六氫環丙[f ]吲唑-3-基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H -苯并[d ]咪唑-5-基)乙醯胺(製備物98)來製備下表中之標題化合物 。 實例 結構及名稱 分析數據 27

2-(2-( 羥甲基 ) - N - 𠰌 啉基 )-N - 甲基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 ) 乙醯胺 製備型HPLC方法1。17 mg (18%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.69 - 7.26 (m, 2H), 3.77 (d, 1H), 3.72 - 3.53 (m, 2H), 3.50 - 3.36 (m, 2H), 3.37 - 3.30 (m, 2H), 3.24 (s, 3H), 3.19 - 2.95 (m, 3H), 2.85 - 2.68 (m, 3H), 2.64 (d, 1H), 2.35 (s, 3H), 2.16 - 2.02 (m, 1H), 1.84 (dt, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1H)；LC/MSm/z (M+H)⁺ = 465.1。 28

2-((R )-2-( 羥甲基 ) - N - 𠰌 啉基 )-N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1H - 苯并 [d ] 咪唑 -5- 基 ) 乙醯胺    製備型HPLC條件：方法2。66 mg (25%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.74 - 7.24 (m, 2H), 3.77 (d, 1H), 3.70 - 3.49 (m, 2H), 3.50 - 3.36 (m, 2H), 3.32 (d, 2H), 3.24 (s, 3H), 3.19 - 2.88 (m, 3H), 2.86 - 2.56 (m, 4H), 2.35 (s, 3H), 2.17 - 1.99 (m, 1H), 1.84 (dt, 1H), 1.29 (s, 3H), 1.22 - 1.10 (m, 1H), 0.42 (dd, 1H), 0.25 (s, 1H)；LC/MSm/z (M+H)⁺ = 465.2。 29

2-(2,2- 二甲基 - N - 𠰌 啉基 )-N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1H - 苯并 [d ] 咪唑 -5- 基 ) 乙醯胺 製備型HPLC條件：方法3；53 mg (42%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.56 (s, 1H), 7.49 (s, 1H), 3.71 (d, 2H), 3.40 - 3.32 (m, 2H), 3.25 (s, 3H), 3.18 - 3.01 (m, 2H), 2.79 (t, 2H), 2.42 (s, 2H), 2.35 (s, 3H), 2.34 - 2.23 (m, 2H), 1.29 (s, 3H), 1.21 (s, 6H), 1.17 - 1.11 (m, 1H), 0.48 - 0.34 (m, 1H), 0.30 - 0.18 (m, 1H)；LC/MSm/z (M+H)⁺ = 463.2。 30

N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1H - 苯并 [d ] 咪唑 -5- 基 )-2-((R )-2- 甲基 - N - 𠰌 啉基 ) 乙醯胺 製備型HPLC條件：方法4；5 mg (8%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.57 (s, 1H), 7.53 - 7.40 (m, 1H), 3.98 - 3.59 (m, 3H), 3.39 - 3.33 (m, 2H), 3.26 (s, 3H), 3.18 - 3.10 (m, 1H), 3.07 (d, 1H), 2.95 - 2.83 (m, 3H), 2.77 (d, 1H), 2.35 (s, 3H), 2.32 - 2.13 (m, 1H), 2.05 - 1.86 (m, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 1.07 (dd, 3H), 0.42 (dd, 1H), 0.25 (q, 1H)；LC/MSm/z (M+H)⁺ = 449.3。 31

N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1H - 苯并 [d ] 咪唑 -5- 基 )-2-((S)-2- 甲基 - N - 𠰌 啉基 ) 乙醯胺    製備型HPLC條件：方法5；19 mg (28%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.57 (s, 1H), 7.49 (s, 2H), 3.79 (dd, 1H), 3.75 - 3.60 (m, 2H), 3.44 - 3.33 (m, 2H), 3.26 (s, 3H), 3.18 - 3.10 (m, 1H), 3.07 (d, 1H), 2.99 - 2.81 (m, 2H), 2.77 (d, 1H), 2.35 (s, 3H), 2.32 - 2.16 (m, 1H), 2.01 (d, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 1.07 (dd, 3H), 0.42 (dd, 1H), 0.25 (td, 1H)；LC/MSm/z (M+H)⁺ = 449.3。 32

2-((2R,6R)-2,6- 二甲基 - N - 𠰌 啉基 )-N - 甲基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 ) 乙醯胺 製備型HPLC條件：方法3；24 mg (34%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.56 (s, 1H), 7.49 (s, 1H), 3.99 (d, 2H), 3.50 - 3.33 (m, 2H), 3.26 (d, 3H), 3.18 - 3.10 (m, 1H), 3.07 (d, 1H), 2.93 - 2.68 (m, 2H), 2.53 (s, 2H), 2.35 (d, 3H), 2.34 - 2.17 (m, 2H), 1.29 (s, 3H), 1.27 - 1.11 (m, 7H), 0.42 (dd, 1H), 0.30 - 0.19 (m, 1H)；LC/MSm/z (M+H)⁺ = 463.2。 33

2-((2S ,6S )-2,6- 二甲基 - N - 𠰌 啉基 )-N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1H - 苯并 [d ] 咪唑 -5- 基 ) 乙醯胺 製備型HPLC條件：方法6；28 mg (39%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.56 (s, 1H), 7.48 (d,^1H ), 3.97 (tt, 2H), 3.42 - 3.33 (m, 1H), 3.25 (s, 3H), 3.18 - 3.10 (m, 1H), 3.07 (d, 1H), 2.98 (dd, 1H), 2.84 - 2.64 (m, 2H), 2.52 - 2.37 (m, 2H), 2.35 (d, 3H), 2.16 (dd, 2H), 1.29 (s, 3H), 1.18 (t, 7H), 0.42 (dd, 1H), 0.24 (td, 1H)；LC/MSm/z (M+H)⁺ = 463.2。 製備型HPLC條件：方法 1 ：Welch Xtimate C18 100 mm × 40 mm × 3 µm, 22%至52%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 10 min；方法 2 ：Welch Xtimate C18 100 mm × 40 mm × 3 µm, 32%至52%於0.05 NH₄ OH中之MeCN/水，25 mL/min, 10 min；方法 3 ：YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 42%至62%於0.05% NH₄ OH中之MeCN/水，35 mL/min, 10 min；方法 4 ：YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 38%至48%於0.05% NH₄ OH中之MeCN/水，35 mL/min, 10 min；方法 5 ：YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 40%至60%於0.05% NH₄ OH中之MeCN/水，35 mL/min, 10 min；方法 6 ： Welch Xtimate C18 150 mm × 40 mm × 10 µm, 21%至61%於0.225%甲酸中之MeCN/水，60 mL/min, 10 min。 藉由針對實例3所闡述之程序自適當酸及製備物46來製備下表中之標題化合物 。 實例 結構及名稱 分析數據 34

N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1H - 苯并 [d ] 咪唑 -5- 基 )-2-N - 𠰌 啉基乙醯胺 製備型HPLC條件：方法7；44 mg (44%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.73 - 7.24 (m, 2H), 3.64 (t, 4H), 3.35 (d, 1H), 3.24 (d, 3H), 3.20 - 3.09 (m, 1H), 3.06 (d, 1H), 3.00 (dd, 1H), 2.75 (dd, 2H), 2.39 (s, 4H), 2.34 (s, 3H), 1.29 (s, 3H), 1.16 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1H); 35

N - 甲基 -N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f ] 吲唑 -3- 基 )-1H - 苯并 [d ] 咪唑 -5- 基 )-2-( 四氫 -2H - 吡喃 -4- 基 ) 乙醯胺 製備型HPLC條件：方法8；36 mg (62%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.48 (s, 2H), 3.94 - 3.75 (m, 2H), 3.43 - 3.33 (m, 3H), 3.24 (d, 3H), 3.13 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 2.32 (s, 3H), 2.05 (d, 2H), 1.87 (q, 1H), 1.68 - 1.46 (m, 2H), 1.29 (s, 3H), 1.13 (ddd, 3H), 0.42 (dd, 1H), 0.25 (t, 1H)；LC/MSm/z (M+H)⁺ = 434.3。 36

N - 甲基 -N -(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-2-(3- 側氧基 - N - 𠰌 啉基 ) 乙醯胺    製備型HPLC條件：方法9，滯留時間：2.30。LC/MSm/z (M+H)⁺ = 449.0 製備型HPLC條件：方法 7 ：Phenomenex Gemini-NX 150 mm × 30 mm × 5 µm, 19%至59%於0.05% NH₄ OH中之MeCN/水，30 mL/min, 10 min。方法 8 ：YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 40%至60%於0.05% NH₄ OH中之MeCN/水，35 mL/min, 10 min。方法 9 ：Agela Durashell C18 150 mm × 25 mm × 5 µm, i5-55%於0.225%甲酸中之MeCN/水，35 mL/min, 8 min梯度。 Instance 26 : 2-((S)-2-( Hydroxymethyl ) - N - 𠰌 Linyl )- N- methyl -N -(6- methyl -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base ) Acetamide

step 1 : 2-((S)-2-( Hydroxymethyl ) - N - 𠰌 Linyl )- N- methyl -N -(6- methyl -2-((4a S ,5a R )-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1 H- Benzo [ d ] Imidazole -5- base ) Acetamide

Use NaI (40 mg, 0.27 mmol) and K₂ CO₃ (40 mg, 0.29 mmol) treatment preparation 98 (130 mg, 0.20 mmol) and(S) -Morpholin-2-ylmethanol (26 mg, 0.22 mmol) in MeCN (5 mL). The mixture was heated at 80°C for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%, then MeOH/EtOAc = 0-20%) to obtainTitle compound (108 mg, 74%).¹ H NMR (400 MHz, chloroform-d) δ 7.71 (s, 1H), 7.36 (d, 1H), 6.22-6.07 (m, 1H), 6.09-5.93 (m, 1H), 5.42 (q, 2H), 3.94-3.73 (m, 4H), 3.71-3.37 (m, 8H), 3.26 (s, 3H), 3.19-3.01 (m, 2H), 2.96-2.68 (m, 4H), 2.34 (s, 4H), 1.38-1.27 (m, 3H), 1.17-1.01 (m, 2H), 0.91 (t, 2H), 0.87-0.73 (m, 2H), 0.40 (s, 1H), 0.26 (d, 1H), -0.02 (s, 9H), -0.11 (t, 9H); LC/MSm/z (M+H)⁺ = 725.4.step 2 : 2-((S)-2-( Hydroxymethyl ) - N - 𠰌 Linyl )- N- methyl -N -(6- methyl -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base ) Acetamide

A solution of the silyl ether (108 mg, 0.149 mmol) of step 1 in DCM (5 mL) was treated with TFA (1.5 mL) at 15°C. The mixture was stirred at 15°C for 2 h and concentrated. Dissolve the residue in MeOH (5 mL) and use concentrated NH₄ OH (2 mL) treatment. The mixture was stirred at room temperature for 2 h. The mixture was concentrated and subjected to preparative HPLC (Welch Xtimate 75 mm × 40 mm × 3 µm, 16% to 56% in 0.05% NH₄ MeCN/water in OH, 25 mL/min, 10 min) Purify the residue to obtainTitle compound (16 mg, 23%).¹ H NMR (400 MHz, CD₃ OD) δ 7.68-7.39 (m, 2H), 3.77 (d, 1H), 3.72-3.52 (m, 2H), 3.52-3.40 (m, 2H), 3.40-3.33 (m, 2H), 3.24 (s, 3H), 3.19-2.93 (m, 3H), 2.86-2.59 (m, 4H), 2.35 (s, 3H), 2.19-2.04 (m, 1H), 1.85 (dt, 1H), 1.29 (s, 3H) , 1.24-1.05 (m, 1H), 0.42 (dt, 1H), 0.24 (t, 1H); LC/MSm/z (M+H)⁺ = 465.3. By the procedures described in Example 18 or similar procedures (by using DIPEA+K₂ CO₃ /NaI) from the appropriate amine and 2-chloro-N -methyl-N -(6-methyl-2-((4aS ,5aR )-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropyl[f ]Indazol-3-yl)-1-((2-(Trimethylsilyl)ethoxy)methyl)-1H -Benzo[d ]Imidazol-5-yl)acetamide (Preparation 98) to prepare one of the followingTitle compound . Instance Structure and name analyze data 27

2- (2- (hydroxymethyl) - N - 𠰌 quinazolinyl) - N - methyl - N - (6- methyl -2 - ((4aS, 5aR) -5a- methyl -1,4,4a ,5,5a,6 -Hexahydrocycloprop [f] indazol- 3 -yl )-1 H -benzo [d] imidazol -5- yl ) acetamide Preparative HPLC method 1.17 mg (18%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.69-7.26 (m, 2H), 3.77 (d, 1H), 3.72-3.53 (m, 2H), 3.50-3.36 (m, 2H), 3.37-3.30 ( m, 2H), 3.24 (s, 3H), 3.19-2.95 (m, 3H), 2.85-2.68 (m, 3H), 2.64 (d, 1H), 2.35 (s, 3H), 2.16-2.02 (m, 1H), 1.84 (dt, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1H); LC/MS m/z (M+H) ⁺ = 465.1. 28

2 - ((R) -2- (hydroxymethyl) - N - 𠰌 quinazolinyl) - N - methyl - N - (6- methyl -2 - ((4a S, 5a R) -5a- methyl -1,4,4a,5,5a,6 -hexahydrocyclopropyl [ f ] indazol- 3 -yl )-1 H -benzo [ d ] imidazol -5- yl ) acetamide Preparative HPLC conditions: Method 2.66 mg (25%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.74-7.24 (m, 2H), 3.77 (d, 1H), 3.70-3.49 (m, 2H), 3.50-3.36 (m, 2H), 3.32 (d, 2H), 3.24 (s, 3H), 3.19-2.88 (m, 3H), 2.86-2.56 (m, 4H), 2.35 (s, 3H), 2.17-1.99 (m, 1H), 1.84 (dt, 1H) , 1.29 (s, 3H), 1.22-1.10 (m, 1H), 0.42 (dd, 1H), 0.25 (s, 1H); LC/MS m/z (M+H) ⁺ = 465.2. 29

2- (2,2-dimethyl - N - 𠰌 quinazolinyl) - N - methyl - N - (6- methyl -2 - ((4a S, 5a R) -5a- -1,4 ,4a,5,5a,6 -hexahydrocycloprop [ f ] indazol- 3 -yl )-1 H -benzo [ d ] imidazol -5- yl ) acetamide Preparative HPLC conditions: Method 3; 53 mg (42%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.56 (s, 1H), 7.49 (s, 1H), 3.71 (d, 2H), 3.40-3.32 (m, 2H), 3.25 (s, 3H), 3.18 -3.01 (m, 2H), 2.79 (t, 2H), 2.42 (s, 2H), 2.35 (s, 3H), 2.34-2.23 (m, 2H), 1.29 (s, 3H), 1.21 (s, 6H) ), 1.17-1.11 (m, 1H), 0.48-0.34 (m, 1H), 0.30-0.18 (m, 1H); LC/MS m/z (M+H) ⁺ = 463.2. 30

N - methyl - N - (6- methyl -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazole 3-yl) -1 H - benzo [d] imidazol-5-yl) -2 - ((R) -2- methyl - N - 𠰌 morpholinyl) as acetamide Preparative HPLC conditions: Method 4; 5 mg (8%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.57 (s, 1H), 7.53-7.40 (m, 1H), 3.98-3.59 (m, 3H), 3.39-3.33 (m, 2H), 3.26 (s, 3H), 3.18-3.10 (m, 1H), 3.07 (d, 1H), 2.95-2.83 (m, 3H), 2.77 (d, 1H), 2.35 (s, 3H), 2.32-2.13 (m, 1H) , 2.05-1.86 (m, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 1.07 (dd, 3H), 0.42 (dd, 1H), 0.25 (q, 1H); LC/MS m/ z (M+H) ⁺ = 449.3. 31

N - methyl - N - (6- methyl -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazole 3-yl) -1 H - benzo [d] imidazol-5-yl) -2 - ((S) -2- methyl - N - 𠰌 morpholinyl) as acetamide Preparative HPLC conditions: Method 5; 19 mg (28%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.57 (s, 1H), 7.49 (s, 2H), 3.79 (dd, 1H), 3.75-3.60 (m, 2H), 3.44-3.33 (m, 2H) , 3.26 (s, 3H), 3.18-3.10 (m, 1H), 3.07 (d, 1H), 2.99-2.81 (m, 2H), 2.77 (d, 1H), 2.35 (s, 3H), 2.32-2.16 (m, 1H), 2.01 (d, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 1.07 (dd, 3H), 0.42 (dd, 1H), 0.25 (td, 1H); LC/ MS m/z (M+H) ⁺ = 449.3. 32

2 - ((2R, 6R) -2,6- dimethyl - N - 𠰌 quinazolinyl) - N - methyl - N - (6- methyl -2 - ((4aS, 5aR) -5a- methyl -1,4,4a,5,5a,6 -hexahydrocycloprop [f] indazol- 3 -yl )-1 H -benzo [d] imidazol -5- yl ) acetamide Preparative HPLC conditions: Method 3; 24 mg (34%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.56 (s, 1H), 7.49 (s, 1H), 3.99 (d, 2H), 3.50-3.33 (m, 2H), 3.26 (d, 3H), 3.18 -3.10 (m, 1H), 3.07 (d, 1H), 2.93-2.68 (m, 2H), 2.53 (s, 2H), 2.35 (d, 3H), 2.34-2.17 (m, 2H), 1.29 (s , 3H), 1.27-1.11 (m, 7H), 0.42 (dd, 1H), 0.30-0.19 (m, 1H); LC/MS m/z (M+H) ⁺ = 463.2. 33

2 - ((2 S, 6 S) -2,6- dimethyl - N - 𠰌 quinazolinyl) - N - methyl - N - (6- methyl -2 - ((4a S, 5a R) - 5a -Methyl- 1,4,4a,5,5a,6 -hexahydrocycloprop [ f ] indazol- 3 -yl )-1 H - benzo [ d ] imidazol -5- yl ) acetamide Preparative HPLC conditions: Method 6; 28 mg (39%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.56 (s, 1H), 7.48 (d, ^1H ), 3.97 (tt, 2H), 3.42-3.33 (m, 1H), 3.25 (s, 3H), 3.18 -3.10 (m, 1H), 3.07 (d, 1H), 2.98 (dd, 1H), 2.84-2.64 (m, 2H), 2.52-2.37 (m, 2H), 2.35 (d, 3H), 2.16 (dd , 2H), 1.29 (s, 3H), 1.18 (t, 7H), 0.42 (dd, 1H), 0.24 (td, 1H); LC/MS m/z (M+H) ⁺ = 463.2. Preparative HPLC conditions:method 1 : Welch Xtimate C18 100 mm × 40 mm × 3 µm, 22% to 52% in 0.05% NH₄ MeCN/water in OH, 25 mL/min, 10 min;method 2 : Welch Xtimate C18 100 mm × 40 mm × 3 µm, 32% to 52% in 0.05 NH₄ MeCN/water in OH, 25 mL/min, 10 min;method 3 ：YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 42% to 62% in 0.05% NH₄ MeCN/water in OH, 35 mL/min, 10 min;method 4 ：YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 38% to 48% in 0.05% NH₄ MeCN/water in OH, 35 mL/min, 10 min;method 5 ：YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 40% to 60% in 0.05% NH₄ MeCN/water in OH, 35 mL/min, 10 min;method 6 : Welch Xtimate C18 150 mm × 40 mm × 10 µm, 21% to 61% MeCN/water in 0.225% formic acid, 60 mL/min, 10 min. Prepare the following table from the appropriate acid and preparation 46 by the procedure described for Example 3Title compound . Instance Structure and name analyze data 34

N - methyl - N - (6- methyl -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazole 3-yl) -1 H - benzo [d] imidazol-5-yl) -2- N - diacetyl quinolinyl amine 𠰌 Preparative HPLC conditions: Method 7; 44 mg (44%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.73-7.24 (m, 2H), 3.64 (t, 4H), 3.35 (d, 1H), 3.24 (d, 3H), 3.20-3.09 (m, 1H) , 3.06 (d, 1H), 3.00 (dd, 1H), 2.75 (dd, 2H), 2.39 (s, 4H), 2.34 (s, 3H), 1.29 (s, 3H), 1.16 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1H); 35

N - methyl - N - (6- methyl -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazole -3 -yl )-1 H - benzo [ d ] imidazol -5- yl )-2-( tetrahydro - 2H - pyran- 4 -yl ) acetamide Preparative HPLC conditions: Method 8; 36 mg (62%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.48 (s, 2H), 3.94-3.75 (m, 2H), 3.43-3.33 (m, 3H), 3.24 (d, 3H), 3.13 (dd, 1H) , 3.06 (d, 1H), 2.77 (d, 1H), 2.32 (s, 3H), 2.05 (d, 2H), 1.87 (q, 1H), 1.68-1.46 (m, 2H), 1.29 (s, 3H) ), 1.13 (ddd, 3H), 0.42 (dd, 1H), 0.25 (t, 1H); LC/MS m/z (M+H) ⁺ = 434.3. 36

N - methyl - N - (6- methyl -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazol-3 - yl) -1 H - benzo [d] imidazol-5-yl) -2- (3-oxo - N - 𠰌 morpholinyl) as acetamide Preparative HPLC conditions: Method 9, retention time: 2.30. LC/MS m/z (M+H) ⁺ = 449.0 Preparative HPLC conditions:method 7 ：Phenomenex Gemini-NX 150 mm × 30 mm × 5 µm, 19% to 59% in 0.05% NH₄ MeCN/water in OH, 30 mL/min, 10 min.method 8 ：YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 40% to 60% in 0.05% NH₄ MeCN/water in OH, 35 mL/min, 10 min.method 9 : Agela Durashell C18 150 mm × 25 mm × 5 µm, i5-55% MeCN/water in 0.225% formic acid, 35 mL/min, 8 min gradient.

使用製備物102 (130 mg, 0.202 mmol)在0℃下處理Et₃ SiH (117 mg, 1.01 mmol)於TFA (5 mL)中之溶液。將混合物在0℃下攪拌2 h並濃縮。將殘餘物溶解於MeOH中，冷卻至0℃並使用濃NH₄ OH (1 mL)處理。濃縮混合物且藉由製備型HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 35%至55%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 10 min)純化殘餘物以得到標題化合物 (38 mg, 36%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.05 (s, 1H), 12.96 (s, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 3.48 (d, 5H), 3.31 - 3.23 (m, 1H), 3.19 (s, 3H), 3.16 (d, 1H), 3.00 (td, 2H), 2.74 (d, 1H), 2.47 - 2.36 (m, 1H), 2.23 - 2.01 (m, 2H), 1.25 (s, 3H), 1.13 (dt, 1H), 0.99 (d, 3H), 0.38 (dd, 1H), 0.17 (t, 1H)；LC/MSm/z (M+H)⁺ = 514.9 (⁸¹ Br)。 Instance 37 : (S)- N -(7- bromine -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use preparation 102 (130 mg, 0.202 mmol) to treat Et at 0°C₃ A solution of SiH (117 mg, 1.01 mmol) in TFA (5 mL). The mixture was stirred at 0°C for 2 h and concentrated. Dissolve the residue in MeOH, cool to 0°C and use concentrated NH₄ OH (1 mL) treatment. The mixture was concentrated and subjected to preparative HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 35% to 55% in 0.05% NH₄ MeCN/water in OH, 25 mL/min, 10 min) Purify the residue to obtainTitle compound (38 mg, 36%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.05 (s, 1H), 12.96 (s, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 3.48 (d, 5H), 3.31-3.23 (m, 1H), 3.19 (s, 3H), 3.16 (d, 1H), 3.00 (td, 2H), 2.74 (d, 1H), 2.47-2.36 (m, 1H), 2.23-2.01 (m, 2H), 1.25 (s, 3H), 1.13 (dt, 1H), 0.99 (d, 3H), 0.38 (dd, 1H), 0.17 (t, 1H); LC/MSm/z (M+H)⁺ = 514.9 (⁸¹ Br).

步驟 1 ： (S)-N-(4- 氰基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H- 苯并 [d] 咪唑 -6- 基 )-N- 甲基 -2-N - 𠰌 啉基丙醯胺

使用Pd(Ph₃ P)₄ (24 m, 0.021 mmol)及Zn(CN)₂ (121 mg, 1.03 mmol)處理製備物103 (160 mg, 0.207 mmol)於NMP (10 mL)中之溶液。將混合物於微波反應器中在160℃下加熱1 h。將混合物冷卻至室溫並分配於水(10 mL)與EtOAc (50 mL)之間。分離有機層並使用額外EtOAc (50 mL)萃取水層。使用鹽水洗滌合併之有機層，乾燥(Na₂ SO₄ )，過濾並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗製材料以得到標題化合物 (120 mg, 81%)。LC/MSm/z (M+H)⁺ = 720.4。步驟 2 ： (S)-N -(7- 氰基 -2-((4aS,5aR)-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N - 甲基 -2-N - 𠰌 啉基丙醯胺

使用步驟1之矽基醚(100 mg, 0.139 mmol)在0℃下處理Et₃ SiH (81 mg, 0.694 mmol)於TFA (5 mL)中之溶液。將混合物在0℃下攪拌2 h並濃縮。將殘餘物溶解於MeOH中並冷卻至0℃。添加NH₄ OH (1 mL)。濃縮混合物且藉由製備型HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 22%至47%於0.2%甲酸中之MeCN/水，25 mL/min, 10 min)純化殘餘物以得到標題化合物 (27 mg, 42%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.35 (s, 1H), 13.09 (s, 1H), 7.73 (s, 2H), 3.53 - 3.40 (m, 5H), 3.20 (s, 3H), 3.14 (d, 1H), 3.02 (d, 2H), 2.75 (d, 1H), 2.37 (dd, 2H), 2.07 (s, 1H), 1.26 (s, 3H), 1.14 (s, 1H), 0.98 (d, 3H), 0.38 (dd, 1H), 0.17 (t, 1H)；LC/MSm/z (M+H)⁺ = 460.2。 Instance 38 : (S)- N -(7- Cyano -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

step 1 : (S)-N-(4- Cyano -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -6- base )-N- methyl -2- N- 𠰌 Hydroxypropionamide

Use Pd(Ph₃ P)₄ (24 m, 0.021 mmol) and Zn(CN)₂ (121 mg, 1.03 mmol) A solution of Preparation 103 (160 mg, 0.207 mmol) in NMP (10 mL) was treated. The mixture was heated in a microwave reactor at 160°C for 1 h. The mixture was cooled to room temperature and partitioned between water (10 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with additional EtOAc (50 mL). The combined organic layer was washed with brine and dried (Na₂ SO₄ ), filtered and concentrated. Purify the crude material by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound (120 mg, 81%). LC/MSm/z (M+H)⁺ = 720.4.step 2 : (S)- N -(7- Cyano -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use the silyl ether (100 mg, 0.139 mmol) from step 1 to treat Et at 0°C₃ A solution of SiH (81 mg, 0.694 mmol) in TFA (5 mL). The mixture was stirred at 0°C for 2 h and concentrated. The residue was dissolved in MeOH and cooled to 0°C. Add NH₄ OH (1 mL). The mixture was concentrated and the residue was purified by preparative HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 22% to 47% MeCN/water in 0.2% formic acid, 25 mL/min, 10 min) to obtainTitle compound (27 mg, 42%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.35 (s, 1H), 13.09 (s, 1H), 7.73 (s, 2H), 3.53-3.40 (m, 5H), 3.20 (s, 3H), 3.14 (d, 1H), 3.02 (d, 2H), 2.75 (d, 1H), 2.37 (dd, 2H), 2.07 (s, 1H), 1.26 (s, 3H), 1.14 (s, 1H), 0.98 (d, 3H), 0.38 (dd, 1H) ), 0.17 (t, 1H); LC/MSm/z (M+H)⁺ = 460.2.

使用製備物105 (120 mg, 0.169 mmol)在0℃下處理Et₃ SiH (196 mg, 1.69 mmol)於TFA (5 mL)中之溶液。將混合物在20℃下攪拌2 h並濃縮。將殘餘物溶解於MeOH中，冷卻至0℃並使用濃NH₄ OH (1 mL)處理。濃縮混合物且藉由製備型HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 25%至45%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 10 min)純化殘餘物以得到標題化合物 (28 mg, 37%)。分析型對掌性SFC管柱：Chiralpak AS-3 100 mm × 4.6 mm × 3 µm；移動相：A/B: CO₂ /EtOH (0.05% Et₂ NH)；梯度：在4 min內5%至40% B且保持40% 2.5 min，然後在1.5 min內5% B；流速：2.8mL/min；管柱溫度：35℃；滯留時間= 2.760 min；LC/MSm/z (M+H)⁺ = 451.2。 Example 39: (S) - N - (7- hydroxy -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazole - 3- yl) -1 H - benzo [d] imidazol-5-yl) - N - methyl -2- N - propan-quinolyl 𠰌 Amides

_{A solution of Et 3} SiH (196 mg, 1.69 mmol) in TFA (5 mL) was treated with Preparation 105 (120 mg, 0.169 mmol) at 0°C. The mixture was stirred at 20°C for 2 h and concentrated. The residue was dissolved in MeOH, cooled to 0°C and _{treated with concentrated NH 4} OH (1 mL). The mixture was concentrated and the residue was purified by preparative HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 25% to 45% _{MeCN/water in 0.05% NH 4} OH, 25 mL/min, 10 min) The title compound (28 mg, 37%) was obtained. Analytical opposite SFC column: Chiralpak AS-3 100 mm × 4.6 mm × 3 µm; mobile phase: A/B: CO ₂ /EtOH (0.05% Et ₂ NH); gradient: 5% to within 4 min 40% B and keep 40% for 2.5 min, then 5% B within 1.5 min; flow rate: 2.8mL/min; column temperature: 35℃; retention time = 2.760 min; LC/MS m/z (M+H) ⁺ = 451.2.

使用製備物106 (150 mg, 0.207 mmol)在0℃下處理Et₃ SiH (120 mg, 1.03 mmol)於TFA (5 mL)中之溶液。將混合物在0℃下攪拌2 h並濃縮。將殘餘物溶解於MeOH中並冷卻至0℃。使用濃NH₄ OH (1 mL)處理混合物，濃縮且藉由製備型HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 32%至55%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 10 min)純化殘餘物以得到標題化合物 (11.4 mg, 12%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 12.70 (s, 1H), 6.96 (s, 1H), 6.60 (s, 1H), 3.96 (s, 3H), 3.49 (d, 5H), 3.39 (d, 0H), 3.29 (td, 1H), 3.27 - 3.19 (m, 1H), 3.19 (s, 3H), 3.10 - 2.89 (m, 2H), 2.73 (d, 1H), 2.47 - 2.38 (m, 1H), 2.24 (d, 2H), 1.25 (s, 3H), 1.16 - 1.04 (m, 1H), 1.03 (d, 3H), 0.37 (dd, 1H), 0.16 (s, 1H)；LC/MSm/z (M+H)⁺ = 465.1。 Instance 40 : (S)- N -(7- Methoxy -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Use preparation 106 (150 mg, 0.207 mmol) to treat Et at 0°C₃ A solution of SiH (120 mg, 1.03 mmol) in TFA (5 mL). The mixture was stirred at 0°C for 2 h and concentrated. The residue was dissolved in MeOH and cooled to 0°C. Use concentrated NH₄ The mixture was treated with OH (1 mL), concentrated and subjected to preparative HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 32% to 55% in 0.05% NH₄ MeCN/water in OH, 25 mL/min, 10 min) Purify the residue to obtainTitle compound (11.4 mg, 12%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 12.70 (s, 1H), 6.96 (s, 1H), 6.60 (s, 1H), 3.96 (s, 3H), 3.49 (d, 5H), 3.39 (d, 0H) , 3.29 (td, 1H), 3.27-3.19 (m, 1H), 3.19 (s, 3H), 3.10-2.89 (m, 2H), 2.73 (d, 1H), 2.47-2.38 (m, 1H), 2.24 (d, 2H), 1.25 (s, 3H), 1.16-1.04 (m, 1H), 1.03 (d, 3H), 0.37 (dd, 1H), 0.16 (s, 1H); LC/MSm/z (M+H)⁺ = 465.1.

使用製備物112 (120 mg, 0.157 mmol)在0℃下處理Et₃ SiH (183 mg, 1.57 mmol)於TFA (5 mL)中之溶液。將混合物在室溫下攪拌2 h並濃縮。將殘餘物溶解於MeOH中並冷卻至0℃。使用濃NH₄ OH (1 mL)處理混合物，濃縮且藉由製備型HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 43%至65%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 10 min)純化殘餘物以得到標題化合物 (50 mg, 63%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.23 (s, 1H), 13.02 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 3.55 - 3.37 (m, 4H), 3.30 (s, 2H), 3.22 (s, 3H), 3.13 (q, 1H), 3.08 - 2.90 (m, 2H), 2.75 (d, 1H), 2.45 - 2.30 (m, 1H), 2.14 - 1.93 (m, 2H), 1.25 (s, 3H), 1.12 (dd, 1H), 0.97 (d, 3H), 0.37 (dd, 1H), 0.17 (t, 1H)；LC/MSm/z (M+H)⁺ = 503.1。 Instance 41 : (S)- N- methyl -N -(2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-7-( Trifluoromethyl )-1 H- Benzo [d] Imidazole -5- base )-2- N - 𠰌 Hydroxypropionamide

Use preparation 112 (120 mg, 0.157 mmol) to treat Et at 0°C₃ A solution of SiH (183 mg, 1.57 mmol) in TFA (5 mL). The mixture was stirred at room temperature for 2 h and concentrated. The residue was dissolved in MeOH and cooled to 0°C. Use concentrated NH₄ The mixture was treated with OH (1 mL), concentrated and subjected to preparative HPLC (Boston Prime C18 150 mm × 30 mm × 5 µm, 43% to 65% in 0.05% NH₄ MeCN/water in OH, 25 mL/min, 10 min) Purify the residue to obtainTitle compound (50 mg, 63%).¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.23 (s, 1H), 13.02 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 3.55-3.37 (m, 4H), 3.30 (s, 2H), 3.22 (s, 3H), 3.13 (q, 1H), 3.08-2.90 (m, 2H), 2.75 (d, 1H), 2.45-2.30 (m, 1H), 2.14-1.93 (m, 2H), 1.25 (s, 3H) , 1.12 (dd, 1H), 0.97 (d, 3H), 0.37 (dd, 1H), 0.17 (t, 1H); LC/MSm/z (M+H)⁺ = 503.1.

使用TFA (0.6 mL)在室溫下處理製備物117 (61 mg, 0.083 mmol)於DCE (0.7 mL)中之溶液。將混合物攪拌16 h並濃縮。將殘餘物溶解於EtOH (0.7 mL)中並冷卻至0℃。使用濃NH₄ OH (0.2 mL)逐滴處理混合物且將混合物在室溫下攪拌4 h。使用水稀釋混合物並使用85:15%異丙醇/DCM (× 3)萃取。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由製備型HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/水，8.5 min，保持於95% 1.5 min, 25 mL/min)純化殘餘物以得到標題化合物 (23 mg, 59%)。滯留時間= 1.74 min；LC/MSm/z (M+H)⁺ = 479.5。 Instance 42 : (S)- N -(7-( Methoxymethyl )-2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

A solution of preparation 117 (61 mg, 0.083 mmol) in DCE (0.7 mL) was treated with TFA (0.6 mL) at room temperature. The mixture was stirred for 16 h and concentrated. The residue was dissolved in EtOH (0.7 mL) and cooled to 0°C. Use concentrated NH₄ The mixture was treated dropwise with OH (0.2 mL) and the mixture was stirred at room temperature for 4 h. The mixture was diluted with water and extracted with 85:15% isopropanol/DCM (×3). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. By preparative HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/water, 8.5 min, hold at 95% 1.5 min, 25 mL/min) Purify the residue to obtainTitle compound (23 mg, 59%). Retention time = 1.74 min; LC/MSm/z (M+H)⁺ = 479.5.

將製備物122 (42 mg, 0.085 mmol)於TFA (0.6 mL)及DCE (0.5 mL)中之溶液在室溫下攪拌2 h並使用Et₃ SiH (0.046 mL, 0.29 mmol)處理。將混合物在室溫下再攪拌2 h。濃縮混合物且使用NaHCO₃ 飽和水溶液稀釋殘餘物。使用EtOAc (× 3)萃取混合物。乾燥(MgSO₄ )合併之有機萃取物，過濾並濃縮。藉由製備型HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/水，8.5 min，保持於95% 1.5 min, 25 mL/min)純化粗製材料以得到標題化合物 (17.3 mg, 63%)。滯留時間= 2.04 min；LC/MSm/z (M+H)⁺ = 469.6。 Instance 43 : (S)- N -(7- chlorine -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

The solution of preparation 122 (42 mg, 0.085 mmol) in TFA (0.6 mL) and DCE (0.5 mL) was stirred at room temperature for 2 h and used Et₃ SiH (0.046 mL, 0.29 mmol) treatment. The mixture was stirred for another 2 h at room temperature. Concentrate the mixture and use NaHCO₃ The residue was diluted with saturated aqueous solution. The mixture was extracted with EtOAc (× 3). Dry (MgSO₄ ) The combined organic extracts are filtered and concentrated. By preparative HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/water, 8.5 min, hold at 95% 1.5 min, 25 mL/min) purify the crude material to obtainTitle compound (17.3 mg, 63%). Retention time = 2.04 min; LC/MSm/z (M+H)⁺ = 469.6.

使用TFA (0.2 mL)及Et₃ SiH (24 mg, 0.21 mmol)在室溫下處理製備物126 (45 mg, 0.062 mmol)於DCE (0.5 mL)中之溶液。將混合物攪拌16 h並濃縮。將殘餘物溶解於DCM及NaHCO₃ 飽和水溶液中。分離各層且使用EtOAc (×2)萃取水層。乾燥(MgSO₄ )合併之有機層，過濾並濃縮。藉由製備型HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/水，8.5 min，保持於95% 1.5 min, 25 mL/min)純化殘餘物以得到標題化合物 (6.1 mg, 21%)。LC/MSm/z (M+H)⁺ = 463.6；滯留時間：1.78 min。 Instance 44 : (S)- N -(7- Ethyl -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use TFA (0.2 mL) and Et₃ A solution of Preparation 126 (45 mg, 0.062 mmol) in DCE (0.5 mL) was treated with SiH (24 mg, 0.21 mmol) at room temperature. The mixture was stirred for 16 h and concentrated. Dissolve the residue in DCM and NaHCO₃ Saturated aqueous solution. The layers were separated and the aqueous layer was extracted with EtOAc (×2). Dry (MgSO₄ ) The combined organic layers are filtered and concentrated. By preparative HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/water, 8.5 min, hold at 95% 1.5 min, 25 mL/min) Purify the residue to obtainTitle compound (6.1 mg, 21%). LC/MSm/z (M+H)⁺ = 463.6; residence time: 1.78 min.

使用TFA (157 mg, 1.38 mmol)在0℃下處理製備物132 (20 mg, 0.028 mmol)於DCE (0.3 mL)中之溶液。將混合物升溫至室溫並攪拌20 h。濃縮混合物並溶解於EtOH中，冷卻至0℃，使用濃NH₄ OH (0.2 mL)處理並將混合物攪拌3 h。使用水稀釋混合物並使用DCM (× 4)及15%異丙醇/DCM (× 3)萃取。乾燥(Na₂ SO₄ )合併之有機層，過濾並濃縮。藉由製備型HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/水，8.5 min，保持於95% 1.5 min, 25 mL/min)純化殘餘物以得到標題化合物 (4.9 mg, 38%)。滯留時間= 1.59；LC/MSm/z (M+H)⁺ = 465.6。 Instance 45 : (S)- N -(7-( Hydroxymethyl )-2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 132 (20 mg, 0.028 mmol) in DCE (0.3 mL) was treated with TFA (157 mg, 1.38 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 20 h. Concentrate the mixture and dissolve in EtOH, cool to 0°C, use concentrated NH₄ It was treated with OH (0.2 mL) and the mixture was stirred for 3 h. The mixture was diluted with water and extracted with DCM (× 4) and 15% isopropanol/DCM (× 3). Dry (Na₂ SO₄ ) The combined organic layers are filtered and concentrated. By preparative HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/water, 8.5 min, hold at 95% 1.5 min, 25 mL/min) Purify the residue to obtainTitle compound (4.9 mg, 38%). Residence time = 1.59; LC/MSm/z (M+H)⁺ = 465.6.

類似於實例1自138 (2.1 g, 3.52 mmol)來製備標題化合物 並藉由製備型HPLC (Chiralpak AD-3 50 mm × 6 mm × 3 µm, 40%等梯度(於EtOH中之0.05%二乙胺/CO_2(g) )，4 mL/min，管柱溫度= 35℃)純化以得到標題化合物 (1.3g, 79%)。滯留時間= 0.38 min及1.46 min；LC/MSm/z (M+H)⁺ = 467.1。 Instance 46 : (S)- N -(7- fluorine -6- methyl -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Prepared similarly to Example 1 from 138 (2.1 g, 3.52 mmol)Title compound And by preparative HPLC (Chiralpak AD-3 50 mm × 6 mm × 3 µm, 40% isocratic (0.05% diethylamine/CO in EtOH)_2(g) ), 4 mL/min, column temperature = 35℃) Purify to obtainTitle compound (1.3g, 79%). Retention time = 0.38 min and 1.46 min; LC/MSm/z (M+H)⁺ = 467.1.

類似於實例41自5-溴-4-氟-3-甲基苯-1,2-二胺來製備標題化合物 。藉由製備型HPLC條件：Welch Xtimate 75 mm × 40 mm × 3 µm, 42%至62%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 10 min)純化以得到標題化合物 (234 mg, 74%)。分析型SFC (Chiralpak AS-3 100 mm × 4.6 mm × 3 µm, A: CO_2(g) ；B：於EtOH中之0.05%二乙胺：梯度：在4 min內5-40% B，保持40% B 2.5 min，5% B 1.5 min；2.8 mL/min，管柱溫度= 35℃)，滯留時間= 2.70 min；LC/MSm/z (M+H)⁺ = 467.2。 Instance 47 : (S)- N -(6- fluorine -7- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N- 𠰌 Hydroxypropionamide

Prepared from 5-bromo-4-fluoro-3-methylbenzene-1,2-diamine similar to Example 41Title compound . By preparative HPLC conditions: Welch Xtimate 75 mm × 40 mm × 3 µm, 42% to 62% in 0.05% NH₄ MeCN/water in OH, 25 mL/min, 10 min) purify to obtainTitle compound (234 mg, 74%). Analytical SFC (Chiralpak AS-3 100 mm × 4.6 mm × 3 µm, A: CO_2(g) ; B: 0.05% diethylamine in EtOH: Gradient: 5-40% B in 4 min, keep 40% B for 2.5 min, 5% B for 1.5 min; 2.8 mL/min, column temperature = 35℃) , Residence time = 2.70 min; LC/MSm/z (M+H)⁺ = 467.2.

使用TFA (0.37 mL)處理製備物144 (72 mg, 0.097 mmol)於DCE (0.6 mL)中之溶液。將混合物在室溫下攪拌20 h。濃縮混合物且將所得殘餘物溶於EtOH (1 mL)中，冷卻至0℃並使用濃NH₄ OH (0.7 mL)處理。將混合物在室溫下攪拌3 h。使用水稀釋混合物並使用DCM (× 4)萃取，隨後使用15%異丙醇/DCM (× 3)萃取。乾燥(Na₂ SO₄ )合併之有機萃取物，過濾並濃縮。藉由製備型HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH₄ OH)/水，8.5 min，保持於95% 1.5 min, 25 mL/min)純化殘餘物以提供標題化合物 (27 mg, 57%)。滯留時間= 2.16 min；LC/MSm/z (M+H)⁺ = 485.6。 Example 48: (S) - N - (7- ( difluoromethyl) -2 - ((4aS, 5aR ) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [ f] Indazol- 3 -yl )-1 H -benzo [d] imidazol -5- yl ) -N -methyl -2- N- 𠰌linyl propionamide

A solution of Preparation 144 (72 mg, 0.097 mmol) in DCE (0.6 mL) was treated with TFA (0.37 mL). The mixture was stirred at room temperature for 20 h. The mixture was concentrated and the resulting residue was dissolved in EtOH (1 mL), cooled to 0°C and _{treated with concentrated NH 4} OH (0.7 mL). The mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with DCM (×4), followed by 15% isopropanol/DCM (×3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by preparative HPLC (XBridge C18 19 mm × 100 mm × 5 µm, 5-95% MeCN (0.03% NH ₄ OH)/water, 8.5 min, hold at 95% 1.5 min, 25 mL/min) To provide the title compound (27 mg, 57%). Retention time = 2.16 min; LC/MS m/z (M+H) ⁺ = 485.6.

使用Et₃ SiH (146 mg, 1.25 mmol)在5℃下處理製備物152 (160 mg, 0.25 mmol)於TFA (2.5 mL)中之溶液。將混合物攪拌2 h且濃縮混合物。使用NaHCO₃ 飽和水溶液稀釋殘餘物並使用EtOAc (3 × 8 mL)萃取。合併有機萃取物，乾燥，過濾並濃縮。藉由製備型HPLC (Phenomenex Gemini, NX-C18, 75 × 30 mm × 3 µm，水/CH₃ CN (0.05% NH₄ OH)，在11 min內10 -50%)純化殘餘物以得到標題化合物 (2.5 mg, 2%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.67 - 7.16 (m, 2H), 4.26 - 4.18 (m, 2H), 3.81 - 3.72 (m, 2H), 3.65 - 357 (m, 4H), 3.40 (s, 3H), 3.24 (d, 3H), 3.19 - 3.01 (m, 2H), 2.77 (d, 1H), 2.57 - 2.36 (m, 4H), 1.30 (s, 3H), 1.27 - 1.08 (m, 3H), 0.42 (dd, 1H), 0.25 (t, 1H).；LC/MSm/z (M+H)⁺ = 509.3。 Instance 49 : (S)- N -(6-(2- Methoxyethoxy )-2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Use Et₃ A solution of Preparation 152 (160 mg, 0.25 mmol) in TFA (2.5 mL) was treated with SiH (146 mg, 1.25 mmol) at 5°C. The mixture was stirred for 2 h and the mixture was concentrated. Use NaHCO₃ The residue was diluted with saturated aqueous solution and extracted with EtOAc (3×8 mL). The organic extracts are combined, dried, filtered, and concentrated. By preparative HPLC (Phenomenex Gemini, NX-C18, 75 × 30 mm × 3 µm, water/CH₃ CN (0.05% NH₄ OH), within 11 min 10 -50%) purify the residue to obtainTitle compound (2.5 mg, 2%).¹ H NMR (400 MHz, CD₃ OD) δ 7.67-7.16 (m, 2H), 4.26-4.18 (m, 2H), 3.81-3.72 (m, 2H), 3.65-357 (m, 4H), 3.40 (s, 3H), 3.24 (d, 3H), 3.19-3.01 (m, 2H), 2.77 (d, 1H), 2.57-2.36 (m, 4H), 1.30 (s, 3H), 1.27-1.08 (m, 3H), 0.42 (dd, 1H) , 0.25 (t, 1H).; LC/MSm/z (M+H)⁺ = 509.3.

使用Et₃ SiH (321 mg, 2.7 mmol)在室溫下處理製備物158 (380 mg, 0.54 mmol)於TFA (5.4 mL)中之溶液。將混合物在室溫下攪拌3 h並濃縮。使用NaHCO₃ 飽和水溶液使殘餘物達到鹼性並使用EtOAc (3 × 15 mL)萃取。濃縮合併之有機層。藉由製備型HPLC (YMC Triart 150 mm × 30 mm × 5 μm, 27%至67%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 10 min)純化殘餘物以得到標題化合物 (108 mg, 45%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.36 (s, 1H), 6.99 (s, 1H), 3.62 (ddd, 4H), 3.36 (d, 1H), 3.31 (s, 3H), 3.26 - 3.10 (m, 2H), 3.07 (d, 1H), 2.78 (d, 1H), 2.63 (s, 3H), 2.54 (dt, 2H), 2.38 (dt, 2H), 1.30 (s, 3H), 1.20 - 1.14 (m, 3H), 1.16 - 1.13 (m, 1H), 0.41 (dd, 1H), 0.26 (t, 1H)；LC/MSm/z (M+H)⁺ = 448.9。 Instance 50 : (S)- N- methyl -N -(7- methyl -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-1 H- Benzo [ d ] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

Use Et₃ A solution of Preparation 158 (380 mg, 0.54 mmol) in TFA (5.4 mL) was treated with SiH (321 mg, 2.7 mmol) at room temperature. The mixture was stirred at room temperature for 3 h and concentrated. Use NaHCO₃ Saturated aqueous solution made the residue basic and extracted with EtOAc (3×15 mL). The combined organic layer was concentrated. By preparative HPLC (YMC Triart 150 mm × 30 mm × 5 μm, 27% to 67% in 0.05% NH₄ MeCN/water in OH, 25 mL/min, 10 min) Purify the residue to obtainTitle compound (108 mg, 45%).¹ H NMR (400 MHz, CD₃ OD) δ 7.36 (s, 1H), 6.99 (s, 1H), 3.62 (ddd, 4H), 3.36 (d, 1H), 3.31 (s, 3H), 3.26-3.10 (m, 2H), 3.07 (d , 1H), 2.78 (d, 1H), 2.63 (s, 3H), 2.54 (dt, 2H), 2.38 (dt, 2H), 1.30 (s, 3H), 1.20-1.14 (m, 3H), 1.16- 1.13 (m, 1H), 0.41 (dd, 1H), 0.26 (t, 1H); LC/MSm/z (M+H)⁺ = 448.9.

類似於實例41自5-溴-3-甲基苯-1,2-二胺及製備物17來製備標題化合物 。使用製備型HPLC條件：Phenomenex Gemini-NX 150 mm × 30 mm × 5 µm, 24%至64%於0.05% NH₄ OH中之MeCN/水，25 mL/min, 9 min)以得到標題化合物 (56 mg, 39%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.48 - 7.25 (m, 1H), 7.07 - 6.95 (m, 1H), 3.72 - 3.57 (m, 4H), 3.26 - 3.19 (m, 1H), 3.14 (br d, 1H), 2.87 (dd, 1H), 2.69 - 2.52 (m, 5H), 2.46 - 2.35 (m, 2H), 1.80 - 1.71 (m, 1H), 1.44 (s, 3H), 1.18 (d, 3H)；LC/MSm/z (M+H)⁺ = 485.2。 Instance 51 : (S)- N -(2-((4a S ,5a R )-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [ f ] Indazole -3- base )-7- methyl -1 H- Benzo [ d ] Imidazole -5- base )- N- methyl -2- N - 𠰌 Hydroxypropionamide

Prepared similarly to Example 41 from 5-bromo-3-methylbenzene-1,2-diamine and preparation 17Title compound . Use preparative HPLC conditions: Phenomenex Gemini-NX 150 mm × 30 mm × 5 µm, 24% to 64% in 0.05% NH₄ MeCN/water in OH, 25 mL/min, 9 min) to obtainTitle compound (56 mg, 39%).¹ H NMR (400 MHz, CD₃ OD) δ 7.48-7.25 (m, 1H), 7.07-6.95 (m, 1H), 3.72-3.57 (m, 4H), 3.26-3.19 (m, 1H), 3.14 (br d, 1H), 2.87 (dd , 1H), 2.69-2.52 (m, 5H), 2.46-2.35 (m, 2H), 1.80-1.71 (m, 1H), 1.44 (s, 3H), 1.18 (d, 3H); LC/MSm/z (M+H)⁺ = 485.2.

步驟 1 ： 6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H- 苯并 [d] 咪唑 -5- 胺

使用NaOH水溶液(10 M, 6.44 mL, 64.4 mmol)在15℃下處理製備物66 (1.50 g, 3.22 mmol)於乙醇(20 mL)中之溶液。將混合物在90℃下攪拌18 h。濃縮混合物且使用EtOAc (3 × 100 mL)萃取殘餘物。濃縮合併之有機層並藉由層析(二氧化矽，EtOAc/PE = 30-50%)純化粗產物以提供標題化合物 (984 g, 72%)。LC/MSm/z (M+H)⁺ = 423.9。步驟 2 ： (S)-N-(6- 甲基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H- 苯并 [d] 咪唑 -5- 基 )-2- N - 𠰌 啉基丙醯胺

類似於實例6步驟1自製備物16 (115 mg, 0.59 mmol)及步驟1之矽基醚(208 mg, 0.491 mmol)來製備標題化合物以提供標題化合物 (216 mg, 78%)。1H NMR (400 MHz, CDCl₃ ) δ 9.62 - 9.51 (m, 1H), 8.41 - 7.62 (m, 1H), 5.42 - 5.35 (m, 2H), 3.85 - 3.78 (m, 3 H), 3.59 - 3.55 (m, 2 H), 3.27 - 3.17 (m, 2H), 2.75 - 2.60 (m, 9H), 2.44 - 2.40 (m, 2H), 1.40 - 1.15 (m, 8 H), 0.92 - 0.85 (m, 2H), 0.42 - 0.38 (m , 1H), 0.01 - -0.08 (m, 9H)；LC/MSm/z (M+H)⁺ = 565.1。步驟 3 ： (S)-N -(6- 甲基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H- 苯并 [d] 咪唑 -5- 基 )-2-N - 𠰌 啉基丙醯胺

類似於實例6步驟2使用步驟2之矽基醚(0.216 g, 0.382 mmol)來製備標題化合物且藉由製備型HPLC (Phenomenex Gemini NX-C18 30 mm × 74 mm × 3 µm, 17-57% MeCN (0.05% NH₄ OH)/水，11 min, 25 mL/min)純化以提供標題化合物 (81 mg, 49%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.91 (s, 1H), 7.45 (br. s, 1H), 3.85 - 3.78 (m, 4H), 3.30 - 3.25 (m, 1H), 3.17 - 3.13 (m, 1H), 3.09 - 2.76 (m, 2H), 2.72 - 2.64 (m, 4H), 2.43 (s, 3H), 1.41 - 1.39 (m, 3H), 1.30 (m, 3H), 1.19 - 1.15 (m, 1H), 0.44 - 0.39 (m, 1H), 0.26 - 0.24 (m, 1H)；LC/MSm/z (M+H)⁺ = 435.1。 Instance 52 : (S)- N -(6- methyl -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

step 1 : 6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- amine

A solution of Preparation 66 (1.50 g, 3.22 mmol) in ethanol (20 mL) was treated with aqueous NaOH (10 M, 6.44 mL, 64.4 mmol) at 15°C. The mixture was stirred at 90°C for 18 h. The mixture was concentrated and the residue was extracted with EtOAc (3×100 mL). Concentrate the combined organic layer and purify the crude product by chromatography (silica dioxide, EtOAc/PE = 30-50%) to provideTitle compound (984 g, 72%). LC/MSm/z (M+H)⁺ = 423.9.step 2 : (S)-N-(6- methyl -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-2- N - 𠰌 Hydroxypropionamide

Similar to Example 6, step 1 from Preparation 16 (115 mg, 0.59 mmol) and the silyl ether (208 mg, 0.491 mmol) of step 1 to prepare the title compound to provideTitle compound (216 mg, 78%). 1H NMR (400 MHz, CDCl₃ ) δ 9.62-9.51 (m, 1H), 8.41-7.62 (m, 1H), 5.42-5.35 (m, 2H), 3.85-3.78 (m, 3 H), 3.59-3.55 (m, 2 H), 3.27 -3.17 (m, 2H), 2.75-2.60 (m, 9H), 2.44-2.40 (m, 2H), 1.40-1.15 (m, 8 H), 0.92-0.85 (m, 2H), 0.42-0.38 (m , 1H), 0.01--0.08 (m, 9H); LC/MSm/z (M+H)⁺ = 565.1.step 3 : (S)- N -(6- methyl -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-2- N- 𠰌 Hydroxypropionamide

Similar to the step 2 of Example 6, the silyl ether (0.216 g, 0.382 mmol) of step 2 was used to prepare the title compound and the title compound was prepared by preparative HPLC (Phenomenex Gemini NX-C18 30 mm × 74 mm × 3 µm, 17-57% MeCN (0.05% NH₄ OH)/water, 11 min, 25 mL/min) purified to provideTitle compound (81 mg, 49%).¹ H NMR (400 MHz, CD₃ OD) δ 7.91 (s, 1H), 7.45 (br. s, 1H), 3.85-3.78 (m, 4H), 3.30-3.25 (m, 1H), 3.17-3.13 (m, 1H), 3.09-2.76 ( m, 2H), 2.72-2.64 (m, 4H), 2.43 (s, 3H), 1.41-1.39 (m, 3H), 1.30 (m, 3H), 1.19-1.15 (m, 1H), 0.44-0.39 ( m, 1H), 0.26-0.24 (m, 1H); LC/MSm/z (M+H)⁺ = 435.1.

步驟 1 ： (S)-N-(2-((4aS,5aR)-5,5- 二氟 -5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-5- 甲基 -1H- 苯并 [d] 咪唑 -6- 基 )-N- 甲基 -2-N - 𠰌 啉基丙醯胺

使用製備物32 (200 mg, 0.68 mmol)於DMF (5 mL)中之溶液處理製備物17 (260 mg, 0.75 mmol)及Na₂ S₂ O₅ (65 mg, 0.34 mmol)之混合物。使用DMSO (1 mL)處理混合物並在110℃下加熱18 h。將混合物冷卻至室溫並傾倒至冰-水中，且使用EtOAc萃取。分離各層並使用鹽水洗滌有機相，乾燥(MgSO₄ )，過濾並濃縮以得到步驟1標題化合物 (550 mg)。LC/MSm/z (M+H)⁺ = 615.3。步驟 2 ： (S)-N-(2-((4aS,5aR)-5,5- 二氟 -5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-5- 甲基 -1H- 苯并 [d] 咪唑 -6- 基 )-N- 甲基 -2- N - 𠰌 啉基丙醯胺

向冷卻至0℃之來自步驟1之矽基醚(0.55 g, 0.72 mmol)中添加TFA (10 mL)，隨後添加Et₃ SiH (0.83 mg, 7.16 mmol)。將混合物升溫至室溫並攪拌1.5 h。濃縮混合物，使用NaHCO₃ 飽和水溶液(20 mL)中和，然後使用EtOAc萃取。合併有機層，使用鹽水洗滌，乾燥(MgSO₄ )，過濾並濃縮。藉由反相HPLC (Phenomenex Gemini C18, 250 × 50 mm × 7 µM，水(0.05% NH₄ OH)/MeCN，在10 min內30%至50%，35 ml/min)純化粗產物以得到標題化合物 (0.19 g, 55%)。SFC方法：Chiral Tech OD-3, 50 mm × 4.6 mm × 3 µm, 5%至40% EtOH (0.05%二乙基胺)/CO_2(g) , 4.0 mL/min，管柱溫度：35℃，滯留時間= 1.58 min (43.1%)及1.65 min (56.8%), 100%ee。LC/MSm/z (M+H)⁺ = 485.3。 Instance 53 : (S)-N-(2-((4aS,5aR)-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-5- methyl -1H- Benzo [d] Imidazole -6- base )-N- methyl -2- N - 𠰌 Hydroxypropionamide

step 1 : (S)-N-(2-((4aS,5aR)-5,5- Difluoro -5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-5- methyl -1H- Benzo [d] Imidazole -6- base )-N- methyl -2- N- 𠰌 Hydroxypropionamide

A solution of Preparation 32 (200 mg, 0.68 mmol) in DMF (5 mL) was used to treat Preparation 17 (260 mg, 0.75 mmol) and Na₂ S₂ O₅ (65 mg, 0.34 mmol) mixture. The mixture was treated with DMSO (1 mL) and heated at 110 °C for 18 h. The mixture was cooled to room temperature and poured into ice-water, and extracted with EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgSO₄ ), filter and concentrate to get step 1Title compound (550 mg). LC/MSm/z (M+H)⁺ = 615.3.step 2 : (S)-N-(2-((4aS,5aR)-5,5- Difluoro -5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-5- methyl -1H- Benzo [d] Imidazole -6- base )-N- methyl -2- N - 𠰌 Hydroxypropionamide

Add TFA (10 mL) to the silyl ether (0.55 g, 0.72 mmol) from step 1 cooled to 0°C, followed by Et₃ SiH (0.83 mg, 7.16 mmol). The mixture was warmed to room temperature and stirred for 1.5 h. Concentrate the mixture, use NaHCO₃ Saturated aqueous solution (20 mL) was neutralized and then extracted with EtOAc. The organic layers were combined, washed with brine, and dried (MgSO₄ ), filtered and concentrated. By reversed-phase HPLC (Phenomenex Gemini C18, 250 × 50 mm × 7 µM, water (0.05% NH₄ OH)/MeCN, 30% to 50% within 10 min, 35 ml/min) purify the crude product to obtainTitle compound (0.19 g, 55%). SFC method: Chiral Tech OD-3, 50 mm × 4.6 mm × 3 µm, 5% to 40% EtOH (0.05% diethylamine)/CO_2(g) , 4.0 mL/min, column temperature: 35℃, retention time = 1.58 min (43.1%) and 1.65 min (56.8%), 100%ee. LC/MSm/z (M+H)⁺ = 485.3.

步驟 1 ： N -(5- 氰基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H- 苯并 [d] 咪唑 -6- 基 )-N - 甲基 -2-( 四氫 -2H- 吡喃 -4- 基 ) 乙醯胺及 N-(6- 氰基 -2-((4aS,5aR)-5a- 甲基 -1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1-((2-( 三甲基矽基 ) 乙氧基 ) 甲基 )-1H- 苯并 [d] 咪唑 -5- 基 )-N- 甲基 -2-( 四氫 -2H- 吡喃 -4- 基 ) 乙醯胺

在室溫下向製備物164 (100.0 mg, 0.1727 mmol)於DMF (5.0 mL)中之溶液中添加2-(四氫-2H-吡喃-4-基)乙酸(25 mg 0.17 mmol)、六氟磷酸N,N,N',N'-四甲基氯甲脒鎓(72.7 mg, 0.259 mmol)及N-甲基咪唑(28.4 mg, 0.345 mmol)，然後將反應混合物在60℃下攪拌16h。使用3% LiCl水溶液(10 mL)處理反應混合物並使用EtOAc (3 × 5 mL)萃取。使用鹽水(10 mL)洗滌合併之有機層並濃縮。藉由層析(二氧化矽，EtOAc/PE = 0-100%)純化粗產物以得到標題化合物 之混合物(104 mg, 85%)。LC/MSm/z (M+H)⁺ = 705.3步驟 2 ： N -(6- 氰基 -2-((4aS ,5aR )-5a- 甲基 -1,4,4a,5,5a,6- 六氫環丙 [f] 吲唑 -3- 基 )-1H - 苯并 [d] 咪唑 -5- 基 )-N- 甲基 -2-( 四氫 -2H- 吡喃 -4- 基 ) 乙醯胺

將來自步驟1之矽基醚(40 mg, 0.07 mmol)於TFA (2.0 mL)中之溶液冷卻至0℃且添加Et₃ SiH (41 mg, 0.35 mmol)。將反應液在0℃下攪拌2 h。濃縮混合物，使用濃NH₄ OH (20 mL)中和並使用EtOAc (× 2)萃取。使用鹽水洗滌合併之有機萃取物，然後乾燥(MgSO₄ )，過濾並濃縮。藉由反相HPLC (Phenomenex Gemini NX, 75 × 30 mm × 3 µM，水(0.05% NH₄ OH)/MeCN，在9 min內13%至53%，30 ml/min)純化粗產物以得到標題化合物 (14.86 mg, 48%)。SFC方法：Chiral Tech OD-3, 50 mm × 4.6 mm × 3 µm, 5%至40% EtOH (0.05%二乙基胺)/CO_2(g) , 2.8 mL/min，管柱溫度：35℃，滯留時間= 5.03 min (100%), 100%ee。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.09 (s, 1H), 13.04 (s, 1H), 8.27 (s, 0.5H), 8.13 (s, 0.5H), 7.95 (s, 0.5H), 7.55 (0.5H), 3.83 (d, 5H), 3.31 (m, 1H), 3.03 (d, 2H), 2.83 (d, 2H), 2.76 (d, 1H), 2.17 (s, 1H), 1.67 (d, 2H), 1.34 (qd, 2H), 1.26 (s, 4H), 1.23 (s, 1H), 1.13 (s, 1H), 0.42 - 0.35 (m, 1H), 0.18 (s, 1H)；LC/MSm/z (M+H)⁺ = 445.2 Instance 54 : N -(6- Cyano -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-N- methyl -2-( Tetrahydro -2H- Pyran -4- base ) Acetamide

step 1 : N -(5- Cyano -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -6- base )- N- methyl -2-( Tetrahydro -2H- Pyran -4- base ) Acetamide and N-(6- Cyano -2-((4aS,5aR)-5a- methyl -1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1-((2-( Trimethylsilyl ) Ethoxy ) methyl )-1H- Benzo [d] Imidazole -5- base )-N- methyl -2-( Tetrahydro -2H- Pyran -4- base ) Acetamide

To a solution of preparation 164 (100.0 mg, 0.1727 mmol) in DMF (5.0 mL) at room temperature was added 2-(tetrahydro-2H-pyran-4-yl)acetic acid (25 mg 0.17 mmol), six Fluorophosphate N,N,N',N'-tetramethylchloroformamidinium (72.7 mg, 0.259 mmol) and N-methylimidazole (28.4 mg, 0.345 mmol), then the reaction mixture was stirred at 60°C for 16h . The reaction mixture was treated with 3% aqueous LiCl (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layer was washed with brine (10 mL) and concentrated. The crude product was purified by chromatography (silica dioxide, EtOAc/PE = 0-100%) to obtainTitle compound The mixture (104 mg, 85%). LC/MSm/z (M+H)⁺ = 705.3step 2 : N -(6- Cyano -2-((4a S ,5a R )-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1 H- Benzo [d] Imidazole -5- base )- N- methyl -2-( Tetrahydro -2H- Pyran -4- base ) Acetamide

Cool the solution of silyl ether (40 mg, 0.07 mmol) in TFA (2.0 mL) from step 1 to 0°C and add Et₃ SiH (41 mg, 0.35 mmol). The reaction solution was stirred at 0°C for 2 h. Concentrate the mixture, use concentrated NH₄ Neutralized with OH (20 mL) and extracted with EtOAc (× 2). The combined organic extracts were washed with brine and then dried (MgSO₄ ), filtered and concentrated. By reversed-phase HPLC (Phenomenex Gemini NX, 75 × 30 mm × 3 µM, water (0.05% NH₄ OH)/MeCN, 13% to 53% in 9 min, 30 ml/min) Purify the crude product to obtainTitle compound (14.86 mg, 48%). SFC method: Chiral Tech OD-3, 50 mm × 4.6 mm × 3 µm, 5% to 40% EtOH (0.05% diethylamine)/CO_2(g) , 2.8 mL/min, column temperature: 35℃, retention time = 5.03 min (100%), 100%ee.¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.09 (s, 1H), 13.04 (s, 1H), 8.27 (s, 0.5H), 8.13 (s, 0.5H), 7.95 (s, 0.5H), 7.55 (0.5H), 3.83 (d, 5H), 3.31 (m, 1H), 3.03 (d, 2H), 2.83 (d, 2H), 2.76 (d, 1H), 2.17 (s, 1H), 1.67 (d, 2H), 1.34 (qd, 2H) ), 1.26 (s, 4H), 1.23 (s, 1H), 1.13 (s, 1H), 0.42-0.35 (m, 1H), 0.18 (s, 1H); LC/MSm/z (M+H)⁺ = 445.2

向冷卻至0℃之製備物173 (82 mg, 0.18 mmol)中添加TFA (5 mL)及Et₃ SiH (206 mg, 1.77 mmol)之混合物。將混合物在室溫下攪拌15 h且去除溶劑。將殘餘物溶於MeOH (10 mL)中並使用NH₄ OH (1 mL)處理。去除溶劑，並藉由製備型HPLC (Boston Prime C-18 150 × 30 mm × 5 µm, H₂ O/含有0.05% NH₄ OH之CH₃ CN，在10 min內40-65%，25 mL/min)純化粗製材料以得到標題化合物 (35 mg, 68%)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (bs, 1H), 7.58 (s, 1H), 3.76 (t, 2H), 3.48 (d, 1H), 3.35-3.26 (m, 2H), 3.20 (s, 4H), 3.02 (d, 2H), 2.76 (d, 1H), 2.11 - 1.95 (m, 1H), 1.66-1.58 (m, 1H), 1.48 (d, 2H), 1.26 (s, 3H), 1.19 - 0.97 (m, 1H), 0.93 (d, 3H), 0.88-0.80 (m, 1H), 0.39 (dd, 1H), 0.17 (t, 1H)。對掌性SFC (Chiralpak AD-3, 50 × 4.6 mm, 3 µm, CO₂ /含有0.05% Et₂ NH之iPrOH，5%至40% 2 min，保持1.2 min，4 mL/min, T = 35℃) Rt = 1.785 min (100% ee)。LC/MSm/z (M+H)⁺ = 459.1。 Example 55: (R) - N - (7- cyano -2 - ((4a S, 5a R) -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] Indazol- 3 -yl )-1H- benzo [d] imidazol -5- yl )-N- methyl -2-( tetrahydro -2H- pyran- 4 -yl ) propionamide

To preparation 173 (82 mg, 0.18 mmol) cooled to 0°C was added a _{mixture of TFA (5 mL) and Et 3} SiH (206 mg, 1.77 mmol). The mixture was stirred at room temperature for 15 h and the solvent was removed. The residue was dissolved in MeOH (10 mL) and _{treated with NH 4} OH (1 mL). The solvent was removed, and by preparative HPLC (Boston Prime C-18 150 × 30 mm × 5 µm, H ₂ O/CH ₃ CN containing 0.05% NH ₄ OH, 40-65% in 10 min, 25 mL/ min) The crude material was purified to obtain the title compound (35 mg, 68%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.66 (bs, 1H), 7.58 (s, 1H), 3.76 (t, 2H), 3.48 (d, 1H), 3.35-3.26 (m, 2H), 3.20 (s, 4H), 3.02 (d, 2H), 2.76 (d, 1H), 2.11-1.95 (m, 1H), 1.66-1.58 (m, 1H), 1.48 (d, 2H), 1.26 (s, 3H), 1.19-0.97 (m, 1H), 0.93 (d, 3H), 0.88-0.80 (m, 1H), 0.39 (dd, 1H), 0.17 (t, 1H). Opposite SFC (Chiralpak AD-3, 50 × 4.6 mm, 3 µm, CO ₂ /iPrOH containing 0.05% Et ₂ NH, 5% to 40% 2 min, hold 1.2 min, 4 mL/min, T = 35 ℃) Rt = 1.785 min (100% ee). LC/MS m/z (M+H) ⁺ = 459.1.

遵循針對實例1所闡述之程序使用碘甲烷-¹³ CD₃ 代替碘甲烷來製備實例56以提供550 mg標題化合物 。分析型HPLC方法：Eclipse XDB-C18 150 mm × 4.6 mm × 3.5 µm；H₂ O/MeCN: 在10 min內10-90%，1.0 mL/min，滯留時間= 7.605 min (99.6%), LC/MSm/z (M+H)⁺ = 453.2。 Instance 56 : (S)-N-( methyl ^-13 C - d ₃ )-N-(6- methyl -2-((4aS,5aR)-5a- methyl -1,4,4a,5,5a,6- Hexahydrocyclopropyl [f] Indazole -3- base )-1H- Benzo [d] Imidazole -5- base )-2- N - 𠰌 Hydroxypropionamide

Follow the procedure described for Example 1 to use methyl iodide-¹³ CD₃ Instead of methyl iodide, Example 56 was prepared to provide 550 mgTitle compound . Analytical HPLC method: Eclipse XDB-C18 150 mm × 4.6 mm × 3.5 µm; H₂ O/MeCN: 10-90% within 10 min, 1.0 mL/min, retention time = 7.605 min (99.6%), LC/MSm/z (M+H)⁺ = 453.2.

Biological analysis In vitro studies IL-2 Inducible T Cell Kinase (ITK) active , IC ₅₀ (nM) ITK activity is determined by measuring the effect of the test compound in the ITK enzyme assay. A 1.0 M HEPES buffer solution (pH 7.5) was prepared as follows: Combine 238.3 g HEPES free acid (Sigma) and 800 mL water, and stir the mixture until completely dissolved. The pH was adjusted to 7.5 and the volume was adjusted to 1000 mL via titration with 5N NaOH. Filter the solution and sterilize. Prepare ITK analysis buffer as follows: use 2 mL 1.0 M HEPES buffer, 500 µL 2% gelatin (Sigma), 1.0 mL MgCl₂ Aqueous solution (1.0 M) and 1.0 mL of glutathione aqueous solution (0.5 M) were treated with 50 mL of HPLC grade water, and the solution was mixed. The solution is made up to 99 mL by adding water in a graduated cylinder and sterilized through a 0.2 µm filter. Add 0.1 mL Brij-35^TM Surfact-Amps^TM Detergent solution (10% w/v aqueous solution, ThermoFisher) and 1.0 mL ATP (Teknova, 100 mM) and mix the solution. Prepare 1.33X ITK enzyme solution as follows: use 4.1 µL ITK enzyme (ITK FL (with N-Flag and C-His tags, about 72kDa) Lake Pharma, 0.25 mg/ml in 25 mM Tris (pH 7.8), In a buffer of 150 mM NaCl, 10% glycerol and 2 mM TCEP) 49.99 mL of ITK assay buffer was treated and the mixture was slightly agitated. Store the resulting solution on ice. Thirty minutes before use, remove the enzyme solution from ice and equilibrate to room temperature by incubating in a room temperature water bath. Prepare 4X ITK substrate solution as follows: Use 100 µL of BTK peptide (China Peptide Company, 2 mM stock solution in DMSO) to treat 50 mL of ITK assay buffer. Cap the tube, mix by inverting the tube slightly, and then store on ice. Thirty minutes before use, remove the substrate solution from ice and equilibrate to room temperature by incubating in a room temperature water bath. During the analysis, 7.5 µL of 1.33X ITK enzyme solution was added to the wells of the plate containing 0.1 µL of test compounds in DMSO at different concentrations. The plate was incubated at room temperature for 30 min. Use 2.5uL 4X ITK substrate solution to treat each well and seal (TopSeal^TM , Perkin Elmer) board. The plate was rotated at 1000 rpm for 30 sec and then incubated at room temperature for 60 min. Remove the seal and use 10 µL stop/detection buffer (20mM HEPES (pH 7.5), 0.01% gelatin, 1 nM LANCE PT66 (Perkin Elmer), 16.5 µg/ml Surelight APC (Perkin Elmer), 10 mM EDTA, 250 mM NaCl) treat each well. The plate was capped again and rotated at 1000 rpm for 30 seconds. The plate was incubated overnight in a blocking carrier at room temperature to minimize water loss. Remove the seal, and use a plate reader to read the fluorescence with an excitation wavelength of 665 nm and an emission wavelength of 615 nm. Plot the concentration of the test compound and the obtained effect value and use the 4-parameter logistic dose response equation to determine the compound concentration required for 50% effect (IC₅₀ ). IC of the compound of the present invention₅₀ The (uM) values are presented in the table below.IL-2 Inhibitory activity , IC ₅₀ (uM) The activity was determined by using the cisbio HTRF™ technology to measure the effect of the test compound on the IL-2 inhibitory activity in the supernatant of activated CD4+ human T cells. Use CD3/CD28 to activate human CD4+ T cells for 3 days and expand for 4-6 days (7-9 days total). On day 0, the frozen CD4+ T cells were thawed, treated with CD3/CD28 Dynabeads, and kept at 37℃/5%CO₂ Nurtured under. On day 3, remove the beads and dilute the cells to 5×10⁵ Cells/cm² , Placed in a G-Rex10 flask, and kept at 37℃/5%CO₂ Nurtured under. From the 7th to the 9th day, remove the cells from the G-Rex flask, count and dilute back to 1×10 in a standard tissue culture flask⁶ Cells/ml. The expanded CD4+ T cells were centrifuged at 300 × g for 10 minutes and resuspended to 0.5 million cells/ml (30,000 cells/well). Add 60 µl of CD4+ T cells to each well of a 384-well plate. Each well contains 0.1 µL of test compound in DMSO at different concentrations. Place the plate at 37°C/5%CO₂ Incubate for 15 min. Dilute 20 µl ImmunoCult^TM (STEMCELL Technologies, 1:12.5 in T cell analysis medium) was added to all wells (final analysis concentration of 1:50). Place the plate at 37°C/5%CO₂ Incubate for another 20 hr to 24 hr. Centrifuge the plate at 300 × g for 10 minutes. Take out 16 µL of the supernatant and combine with 4 µl IL-2 HTRF Abs. (cisbio kit). The plate was incubated at room temperature for 3 hours and read using EnVision plate reader at 665 nm and 615 nm wavelength. Plot the concentration of the test compound and the obtained effect value and use the 4-parameter logistic dose response equation to determine the compound concentration required for 50% effect (IC₅₀ ). IC of the compound of the present invention₅₀ The (uM) values are presented in the table below.

Tropomyosin receptor kinase A (TRKA) activity,% inhibition analysis known in the art for measuring the activity of TRKA; see, for example, those set forth in the following documents: ● Skerratt SE et al., J Med Chem (2016). .. , 59(22):10084-10099 PMID: 27766865. DOI: 10.1021/acs.jmedchem.6b00850 ● Bagal SK et al., J. Med. Chem. (2018), 61(15): 6779-6800 PMID: 29944371. DOI: 10.1021/acs.jmedchem.8b00633 by using ThermoFisher Z'-LYTE analysis of the fluorescence-based coupling enzyme form ( www.thermofisher.com/selectscreen ) to measure the test compound against TRKA (also known as type 1 neurotrophin) The effect of amino acid kinase receptor (NTKR1)) enzyme activity was used to determine NTRK1 activity. The test compound was screened at a fixed concentration of 1 uM and the% inhibition compared to the control at a fixed ATP concentration of 1 mM was determined. Compare the resultant effect value of the test compound with the analytical control to determine the percent inhibition (%). The inhibition percentage (%) value of the compound of the present invention is presented in the table below. Table : In vitro study data Instance number ITK IC ₅₀ (uM) ¹ ITK count (n) IL-2 IC ₅₀ (uM) ² IL-2 count (n) TRKA inhibition percentage (%) ³ TRKA count (n) 1 0.006 13 0.039 14 108 2 2 NT NT NT 3 0.016 3 0.113 3 97 2 4 0.003 3 0.022 3 95 2 5 0.005 2 0.027 2 NT 6 0.011 3 0.101 3 102 2 7 0.002 9 0.013 7 106 2 8 0.005 2 0.026 2 NT 9 0.020 2 0.099 3 99 2 10 0.007 3 0.067 3 104 2 11 0.003 3 0.034 3 107 2 12 0.003 3 0.025 4 94 2 13 0.001 63 0.003 6 99 6 14 0.003 61 0.042 7 92 4 15 0.004 4 0.042 4 107 2 16 0.005 4 0.065 6 116 2 17 0.005 2 0.045 3 NT 18 0.009 3 0.091 3 100 2 19 0.009 3 0.057 3 98 4 20 0.005 3 0.053 3 98 2 twenty one 0.009 3 0.098 3 91 2 twenty two 0.044 3 0.340 3 93 2 twenty three 0.124 3 0.304 3 101 2 twenty four 0.008 3 0.106 4 105 2 25 0.013 3 0.101 3 101 2 26 0.012 4 0.212 2 99 2 27 0.017 3 0.289 2 NT 28 0.019 3 0.305 3 NT 29 0.012 3 0.058 4 NT 30 0.015 3 0.082 4 NT 31 0.013 3 0.075 4 99 2 32 0.016 3 0.083 4 99 2 33 0.011 3 0.068 4 NT 34 0.010 2 0.103 3 98 2 35 0.006 3 0.050 3 NT 36 0.005 3 0.096 3 97 2 37 0.009 2 0.130 3 96 2 38 0.007 3 0.085 3 96 2 39 0.008 3 0.082 3 97 2 40 0.019 3 0.103 3 96 2 41 0.034 4 0.176 4 96 2 42 0.038 3 0.200 4 98 2 43 0.016 3 0.171 3 96 2 44 0.028 4 0.219 3 94 4 45 0.017 4 0.365 3 97 2 46 0.006 3 0.047 4 95 4 47 0.029 3 0.161 3 98 2 48 0.017 4 0.207 3 95 2 49 0.012 2 0.100 2 98 2 50 0.016 5 0.126 3 97 2 51 0.002 4 0.019 4 97 2 52 0.121 3 0.274 3 109 2 53 0.001 3 0.010 4 96 2 54 0.272 3 4.570 2 NT 55 0.005 4 0.041 3 89 2 56 NT NT NT Note : ¹ ITK IC ₅₀ value is presented as the geometric mean of count n ² IL-2 IC ₅₀ value is presented as the geometric mean of count n ³ TRKA inhibition% value is presented as the arithmetic mean of count n NT means not tested above The entire contents of all references mentioned are incorporated by reference.

Figure 1 shows the PXRD pattern of the compound of Example 1.1 (Form 1). Figure 2 shows the PXRD pattern of the compound of Example 1.2a (Form 2). Figure 3 shows the PXRD pattern of the compound of Example 1.3 (Form 3). Figure 4 is the ORTEP diagram of the compound of Example 1.4 (Form 2), which is drawn using the displacement parameter at 50% probability and the water molecule is omitted for clarity. Figure 5 is the ORTEP diagram of the compound of Example 1.4 (Form 2), which is drawn using the displacement parameter at 50% probability and shows water molecules. Figure 6 shows the TGA of the compound of Example 1.1 (Form 1). Figure 7 shows the TGA of the compound of Example 1.3 (Form 3).

Claims (27)

A compound of formula (I),

Or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt, wherein: each R ^{1 is} independently H or F; R ² is H, (C ₁ -C ₄ )alkane Group, hydroxy (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy (C ₁ -C ₄ )alkyl or substituted by one, two or three F (C ₁ -C ₄ ) Alkyl; each R ^{3 is} independently H, F, (C ₃ -C ₅ )cycloalkyl, (C ₁ -C ₄ )alkyl or substituted by one, two or three F (C ₁ -C ₄ )alkyl; or two R ³ together with the carbon atoms to which they are connected form (C ₃ -C ₅ )cycloalkyl; R ⁴ is selected from

or

, Where each heterocyclic ring is optionally composed of one or two independently selected from pendant oxy groups, (C ₁ -C ₄ )alkyl, hydroxy (C ₁ -C ₄ )alkyl, and one, two or three F Substituents of substituted (C ₁ -C ₄ ) alkyl; and R ⁵ and R ^{6 are} independently H; halogen; OH; CN; (C ₁ -C ₆ ) alkyl; hydroxy (C ₁ -C ₆ ) alkyl; (C ₁ -C ₄₎ alkoxy (C ₁ -C ₆₎ alkyl; by one, two or three substituents of F (C ₁ -C ₆₎ alkyl; (C ₁ -C ₆₎ alkoxy; or a substituent of (C ₁ -C ₄₎ alkoxy (C ₁ -C ₆₎ alkoxy. For the compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein each R ¹ is H. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ² is H or (C ₁ -C ₄ )alkyl. The compound of claim 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein R ² is a methyl group. If the compound of claim 1 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein each R ^{3 is} independently H, F or (C ₁ -C ₄ )alkane base. The compound of claim 5 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein each R ^{3 is} independently H, F or methyl. For the compound of claim 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, wherein one R ³ is H and the other R ³ is a methyl group. Such as the compound of claim 7, which has the formula (Ia):

Or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or the salt. If the compound of claim 1 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

, Which is optionally substituted by one or two substituents independently selected from pendant oxy, (C ₁ -C ₄ )alkyl and hydroxy (C ₁ -C ₄ )alkyl. If the compound of claim 9 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

. If the compound of claim 10 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁴ is

. If the compound of claim 1 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁵ and R ^{6 are} independently H; halogen; OH; CN; (C ₁ -C ₃ )alkyl; hydroxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkoxy(C ₁ -C ₃ )alkyl; substituted by one, two or three F ( C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkoxy; or (C ₁ -C ₃ )alkoxy substituted by (C ₁ -C ₃ )alkoxy. If the compound of claim 12 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁵ is H, halogen, CN, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or (C ₁ -C ₃ )alkoxy substituted by (C ₁ -C ₃ )alkoxy. If the compound of claim 1 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, wherein R ⁶ is H; halogen; OH; CN; (C ₁ -C ₃ )alkane Group; hydroxy (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy (C ₁ -C ₃ ) alkyl; substituted by one, two or three F (C ₁ -C ₃ ) Alkyl; or (C ₁ -C ₃ )alkoxy. If the compound of claim 1 or its pharmaceutically acceptable salt or the compound or the pharmaceutically acceptable solvate of the salt, which is selected from: (S) -N -methyl- N- (6-methyl -2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d] (Imidazol-5-yl)-2- N -𠰌linyl propionamide; (R) -N -methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a, 5,5a,6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H -pyran-4- yl) propan Amides; (R) - N - ( 7- fluoro -2 - 4aS, 5aR (() -5a- methyl -1,4,4a, 5,5a, 6- hexahydro-cyclopropa [f] indazol-3-yl) -1 H - benzo [d] imidazol-5-yl) - N - methyl-2- (tetrahydro -2 H - pyran-4-yl) propan-acyl amine; (S ) -N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f)indazol-3-yl)- 1 H -Benzo[d]imidazol-5-yl) -N -methyl-2- N -𠰌linylpropionamide; (S) -N -ethyl- N -(7-fluoro-2-( (4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop(f)indazol-3-yl)-1 H -benzo(d)imidazole-5- yl) -2- N - propan Amides 𠰌 quinolyl; (S) - N - ( 6,7- difluoro -2 - ((4aS, 5aR) -5a- methyl -1,4,4a, 5, 5a, 6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -methyl-2- N -𠰌linylpropionamide; (S) -N -(6,7-Difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazole- 3-yl)-1 H -benzo[d]imidazol-5-yl) -N -ethyl-2- N -𠰌linyl propionamide; (S)- N -(7-fluoro-6-methyl Base-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo [ d ]imidazol-5-yl) -N -methyl-2- N -linolinylpropanamide; and (S) -N -methyl- N -(7-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl )-2- N -𠰌linylpropanamide. Such as the compound of claim 15, which is (S) -N -methyl- N- (6-methyl-2-((4a S ,5a R )-5a-methyl-1,4,4a,5, 5a,6-Hexahydrocycloprop[ f ]indazol-3-yl)-1 H -benzo[ d ]imidazol-5-yl)-2- N -linolinyl propionamide or its pharmaceutically acceptable The salt or the compound or the pharmaceutically acceptable solvate of the salt. Such as the compound of claim 15, which is (R) -N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclic prop [f] indazol-3-yl) -1 H - pyran-4-on-yl) propan-acyl amine or a pharmaceutically - benzo [d] imidazol-5-yl) -2- (tetrahydro -2 H An acceptable salt or a pharmaceutically acceptable solvate of the compound or the salt. Such as the compound of claim 16, which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a, 6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N- 𠰌linylpropionamide or its hydrate. Such as the compound of claim 18, which is dihydrate (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5, 5a, 6-Hexahydrocycloprop[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2- N- 𠰌linylpropionamide. Such as the compound of claim 16, which is

. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 21, which is suitable for topical administration. The pharmaceutical composition of claim 21 or 22, which comprises one or more other therapeutic agents. A use of the compound according to any one of claims 1 to 20, which is used to prepare a medicament for the treatment of ITK inhibitor indications. Such as the use of claim 24, wherein the indication for the ITK inhibitor is a dermatological disorder. The use of claim 25, wherein the dermatological condition is dermatitis. Such as the use of claim 26, wherein the dermatitis is atopic dermatitis.

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